PT94373A - METHOD FOR THE PREPARATION OF ALCANOIC ACID COMPOUNDS WITH PHENYL AND HETEROARILTHE SUBSTITUENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

Compounds represented by the following structural formula (I): <CHEM> wherein q is O or 2; R1 is (L)a-(CH2)b-(T)c-M a is 0 or 1; b is 3 to 14; c is 0 or 1; L and T are independently oxygen or CH2; M is C1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl optionally monosubstituted with Br, Cl, CF3, alkoxy, alkyl, methylthio, or trifluoromethylthio; Y is (CHX)(CH2)p-Z wherein Z is COR3, or tetrazolyl; in which R3 is OH, NH2, aryloxy, or C1-6 alkoxy; p is 0, 1 or 2; X is OH, or alkoxy; R is -(CH2)p-W; d is 0 to 6; W is phenyl substituted with B, C, or D; B is-(CH2)p-V wherein p is 0 to 6 and V is COR3, SO3H, SO2H, SO2NH2, COCH2OH, CHOHCH2OH, or tetrazolyl, with R3 as defined above; C and D are independently selected from H, OH, F, Cl, Br, CF3, alkyl, alkoxy, methylthio, trifluoromethylthio, NO2, NH2, NHalkyl, or CalkylCO-; or pharmaceutically acceptable salts thereof, can be used in the preparation of a medicament for the treatment of asthma.

Description

71 102 SBC Case 14343-ClP 1

DESCRIPTIVE MEMORY

Background of the Invention

It has been shown that &quot; Slow Anaphylactic Action Substance &quot; (3R3-A) is a highly potent bronchoconstricting substance which is primarily released by basophilic mastoids in the &quot; challenge &quot; antigenic. SRS-A was proposed as a main mediator in human asthma. In addition to its pronounced effects on lung tissue, SRS-A also produces changes in skin permeability and may be involved in acute skin allergic reactions. In addition, SRS-A showed depressed ventricular contraction and potentiation of the cardiovascular effects of histamine. The discovery of naturally occurring leukotrienes and their relationship to SRS-A has reinforced the interest in SRS-A and the other metabolites of arachidonate. SRS-A 'derived from mouse, rat, guinea pig and man have all been characterized as mixtures of leukotriene-C4 CLTC4), leucotrisno-D4 (LTD4) and 1-succinyl-E4 (LTE4), shown below. sstr ut ur ais »

Leukotrienes are a group of icosanoids, formed from the metabolism of arachidonic acid via lipoxygenase pathway. These 'lipid derivatives' provide the LTA4 and are of two types; (1) those containing a sulphide-peptide side chain (LTC4, LTD4 and LTE4) and (2) those which are non-peptidic (LTB4). The leucoids comprise a group of naturally occurring substances that have the potential to contribute significantly. for the pathogenesis of a variety of inflammatory and ischemic disorders. The pathophysiological role of leukotrienes has been the focus of recent intensive studies.

As summarized by Lsft, A. M.

Biochemical Pharmacolov? 1 102 1S6 14343-CIP 1

(1986), both the psychotic leukotrienes and the leukotrienes exert microcirculatory actions, promoting fluid transport through the capillary endothelial membrane at the highest rates of the types of vascular layers. LTB4 hundred acc. and contributes to the recruitment and

Cj ϋ '*'> &gt; * &quot; "Adherence of the mobile treatment plants to the endothelial membrane. LTE4 stimulates a variety of muscle types. 0! TC4 ® LTD4 are potent bronchoconstrictors and effective vascular smooth muscle stimulators. This vasoconstrictor effect will have renal O & me: The 1st lungs have po t < agonists such as Proc. LTD4 have 1 human, x 126, 449-d 3 SvO O Ή ks. Bronchial asthma sucotenes are implicated in a number of diseases. Leukotrienes are known as bronchoconstricts in humans. LTC4 and LTD4 have been shown to be potent and selective, active peripheral airways than histamine. [See Drazen, J. M., et al.

JiCad. Know. USA 7, 4354-4358 (1980)], the LTC, -? It has been shown to increase the release of mucus from the airways. et .alpha.

Sev. To breathe

The presence of leukotrienes in the expectoration of patients having cystic fibrosis, chronic bronchitis and bronchiectasis at levels likely to have pathophysiological effects has been reported in the literature. demonstrated by Zakrzewski et al. [See Zakrzewski, J. T. et al., Pros-taglandins, 28, 5, 641 (1984)]. Treatment of such diseases constitutes a possible additional utility for leukotriene antagonists.

Leukotrienes were identified in the nasal secretions of allergic subjects who were challenged in vivo with a specific antigen. Leukotriene release was correlated with typical allergic signs and symptoms. [See Believers, P. S. st. Al. New England J. of Sied. . 310, 25, 1626-1629 (1984)]. This suggests that allergic rhinitis is another area of utility for leukotriene antagonists. The role of leukotrienes and the specificity of selectivity of a particular leukotriene antagonist in an animal model of adult respiratory distress syndrome has been investigated by Snapper et al., [See Snapper, J. et al., Abstracts of Trtd. on Prostaglandins and Related Comp. Florence, Italy, P9-495 (June 1986)]. Elevated LTD4 concentrations were shown in pulmonary edema fluid from patients with adult respiratory distress syndrome. [See H-thathay, M. et al., J Clin. Immunol., 4, 479-483 (1981)]. Markedly elevated leukotriene levels were shown in the edema fluid of a patient with pulmonary edema after cardiopulmonary bypass. [See Swerdlow, B. N., et al., Anesth. end., 65, 306-308, (1986)]. LTC and LTD have also been shown to have a direct systemic arterial hypotensive effect and to produce vasoconstriction and increased vasoperatility. [See Prazen et al., Ibid.]. This suggests that leukotriene antagonists may also be useful in the areas of adult respiratory distress syndrome, pulmonary edema and hypertension.

Leukotrienes are also directly or indirectly implicated in a variety of non-pulmonary diseases in the ocular, dermatological, cardiovascular, renal, traumatic, inflammatory, carcinogenic and other areas.

Further evidence of leukotrienes as mediators of allergic reactions is provided by the identification of leukotrienes in subjects' lacrimal fluids following a conjunctival irritation test and skin bubble fluids after an allergenic challenge in allergic skin and conjunctival mucosal diseases . [See Sisgaard, H., st al., Allergy. 40, 417-423 (1985)]. The immunoreactivity of leukotrienes has been shown to be present in the aqueous humor of human patients with and without uvsitis. The concentrations of leukotrienes were sufficiently high such that these mediators were supposed to contribute significantly to tissue responses. [See -71- 71.9 ° C. Case 14343-CIP-C19]. arrhythmias A. M. Sirogllg. 35, 2, 123-127 (1986)]. Thus, additional areas of utility for leukotriene antagonists may be the treatment of myocardial ischemia, acute myocardial infarction, ischemic myocardial recovery. angina; cardiac, shock and atherosclerosis. at

Leukotriene antagonists may also be useful for renal ischemia and renal failure. Sadr et al. Showed that LTC4 produces a significant elevation of at least one cardiac output and cardiac output and that such effects can be abolished by a leukotriene specific. [See Badr, K.R. et al., Research antagonist Circulation 3 * 5 · 492-499 (1984)]. Leukotrienes have also been shown to play a role in enooLoxin-induced renal failure and the effects of selectively antagonized leukotrienes in this model of renal injury. [See Badr, K, F., Et. Mill. International, 30, 474-480 (1986)], LTD4 has been shown to produce local glomerular constricting actions that are prevented by treatment with a leukotriene antagonist. [See Badr, K.F. et al., Ridnev International. 29, 1, 328 (1986)].

It has been found that LTC4 binds rat mesangial mesangial cells in culture and thus provides intraglomerular actions to reduce filtration surface area, [See Dunn, M.J., et al. Kidnev Internationa1. 27, 1, 256 (1935)]. Thus, another area of utility for leukotriene antagonists may be the treatment of glomerulonephritis.

Leukotrienes were indicated in the transplantation area. It was documented by Foegh et al, rejection an increase in a. survival of the homograft: cardiac leukotriene receptor antagonist. [See Foegh, M. L. et al., Prostaglandin. Thromboxans, and Leukotrisns Research, 13, 209-217 (1985)]. Rejection of renal and renal homografts in the presence of rats has been shown to produce increased amounts of LTC4. [See Coffman, T.I. et al., Kidnev International, 29, 1, 332 (1986)],

An additional area of utility for leukotriene antagonists may be the treatment of tissue trauma,

Parker, J. A., et al. Arch Ophthalmol, 104, 722-724 (1986)]. It has also been shown that psoriatic skin has high levels of lsucotrienes. [See Ford-Hutchinson, J. Allergy Clin., Immunol., 74437-440 (1984)]. The local effects of intracutaneous injections of synthetic lsucotrienes on human skin have been demonstrated by Soter et al. [See Soter et al., J. Clin. Invest. Pernato et al., 80, 115-119 (1983)]. Cutaneous vasodilation with formation of edema and neutrophil infiltration were induced. Leukotriene synthesis agents or leukotriene antagonists may also be useful in ocular treatment

Jermatological conditions such as conjunctivitis; uveitis, allergic dermatitis or psoriasis.

Another area of utility for leukotriene antagonists is the treatment of cardiovascular diseases. Since peptidic lsucotrienes are potent coronary vasoconstrictors, they are implicated in a variety of cardiac disorders including arrhythmias, conduction block, and cardiac depression. Synthetic leukotrienes have been shown to be powerful myocardial depressants, their effects being a decrease in contractile force and coronary flow. It has been shown that the. cardiac effects of LTC4 and LTB4 are antagonized by a leukotriene specific antagonist utility, thus suggesting leukotriene antagonists in the areas of imiocardium depression and cardiac anaphylaxis. [See Burke, JA, et al., Pharmaco-logy and Experimental Therapeutics, 221, 1, 235-241 (1982)], 0 .. TC, .TD &lt; s were measured on body fluids endotoxic, but are rapidly eliminated from the blood into the bile. Thus, leukotrienes are formed in ischemia and shock. Specific inhibitors of leukotriene biosynthesis reduce the level of leukotrienes and, consequently, reduce the manifestations of traumatic shock, endotoxic shock and acute myocardial ischemia. Leukotriene receptor antagonists have also been shown to reduce manifestations of endotoxic shock and reduce the extent of infarction. Administration of the peptidic leukotrienes has been shown to produce significant ischemia or shock. [See Lafer, 71 102 SBC Case 14343-ClP 1

-9-burns or fractures. A significant increase in the production of cysteinyl leukotrienes following mechanical or thermal trauma sufficient to induce tissue edema and circulatory / respiratory dysfunction has been shown. [See Denzlinger, C. et al., Science, 230, 330-332 (1985)].

Leukotrienes also play a role in acute inflammatory actions. LTC4 and LTD4 have potent effects on vascular caliber and permeability, and LTB4 enhances leukocyte adhesion to the endothelium. arteriolar constriction, plasma percentile, and leukocyte adhesion bear a close resemblance to the early events of acute inflammatory reactions. [See Dahlen, S. E. et al., Proc. Natl, stay. Know. USA. 78, 6, 3887-3891 (1981)]. Mediation of local homeostasis and inflammation by leukotrienes and other mast cell-dependent compounds were also investigated by Lewis et al. [See Lewis, R.A. et al., Nature. 293, 103-108 (1981)]. Accordingly, leukotriene antagonists may be useful in the treatment of inflammatory diseases including rheumatoid arthritis and gout.

It has been shown that cysteinyl leukotrienes also undergo enterohepatic circulation, and are thus indicated in the area of inflammatory liver disease. [See Denzlinger, C. et al., Prostaglandins Leukotrienes and Medicine, 21, 321-322 (1986)]. Leukotrienes may also be important mediators of inflammation in inflammatory bowel disease. [See Peskar, B. M. et al., Et al., Acta., 18, 381-383 (1986)]. The leukotriene antagonists may thus be useful in the treatment of inflammatory bowel disease of the liver.

Leukotrienes have been shown to modulate IL-1 production by human monocytes. [See Rola-Pleszczynski, M. et al., J. of. Imraun., 135, 6, 3958-3961 (1985)]. This suggests that leukotriene antagonists may play a role in the XL-1-mediated functions of monocytes in inflammation and immune reactions. LTA4 has been shown to be a factor in the induction of carcinogenic tumors and is considered a link between acute immune defense reactions and carcinogenesis. Accordingly, leukotriene antagonists may possibly have utility in the treatment of some types of carcinogenic tumors. [See Hiechnewsky, G.G. et al. Anticancer Res, 5, 6, 639 (1985)].

Leukotriene have been implicated in gastric bypass and gastric ulcers. The destruction of the gastrointestinal mucosa because of potent vasoconstriction and sphing of blood flow is correlated with increased levels of LTC4. Functional antagonism of the effects of leukotriene may represent an alternative in the treatment of mucosal lesion. [See Dreyling, K.W. st al. Eritish J. Pharmacol. 88, 236P (1986) and Peskar, B.M. et al., Prostanolols. 31, 283-293 (1936)]. A leukotriene antagonist has been shown to protect against gastric stress induced ulcer in rats. [See Ogle, C. W. et al., IRCS Med. Sci., 14, 114-115 (1986)].

Other areas in which leukotriene antagonists may be of use in the treatment of leukotriene antagonists are the biliary [See Doty, J (1983), Marom, 1. et (1982)]. * leukotrienes are indicated as 126. 449-451 LS-? 1986)], and the treatment of il., Amer. J. of Surcrarv. 145. 54-61. Rev. ResDir,

It antagonizes the effects of LTC4, LTD1, and LTE.sup.2 or other pharmacologically active mediators on the terminal organ, e.g., airway smooth muscle, compounds and pharmaceutical compositions of the present invention are valuable in the treatment of diseases in subjects, including humans or animals, in which leukotrienes are a key factor,

Suffice of the Invention of preparation of ds

This invention relates to the process compounds represented by the formula (I)

<3 is w 0, 1 or 2s O (L - (CH 2) b is 0 or 1; b is 3 to 1 L 4; c is 0 or 15 L and T are independently sulfur, oxygen or CH 2 with 3 with the proviso that L and 1 are sulfur when q is 1 or 25 is M is C1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl, optionally monosubstituted by Sr, Cl, CF3 C1-4 alkyl, C1-4 alkoxy, F, when they are H, then, in particular from H, Br, X, OH, MO2 or MH23 or, T and M are as defined above and Y is COR 3 or (CH) n (CH 2) p Z wherein R 3,

X is OH, MH 2, aryloxy or alkoxy is 0 or 15 is 0, 1 or 25 is H, OH, C 1-4 alkyl, C 2-4 alkoxy or F; COR 3 or tetrazolyl; -12- 71 102 SBC Case 14343-CIP 1

R is - (C) d-W

R 1 and R 2 are each independently hydrogen or C 1-4 alkyl at any point when d is not 0 = d is 0 to 6; W is a six-membered aryl or heteroaryl ring selected from phenyl, pyridyl or pyrimidinium unsubstituted or substituted by 8, C or D, or W is one of

B is - (C) p -V I wherein R 5 and R 6 are each independently hydrogen or alkyl p is 0 to 6; V is H, C 1-4 alkyl, COOR 3 &gt; SO 3 H, SO 2 H, SO 2 NH 2, COCH 2 OH, CHOH H 2 GH or tetrazolyl, with R 3 as defined above; C and D are independently selected from OH, F, Cl, Br, CF3, C1-4 alkyl, alkoxy methylthio, trifluoromethyl, SO2 NH2, NH4 -C4 alkyl or alkyl Or a pharmaceutically acceptable salt thereof,

This invention further relates to the process for the preparation of pharmaceutical compositions comprising a non-toxic effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

7i 1G2 SBC Case 14343-CIP 1 -13 '

This invention also relates to the process for the preparation of pharmaceutical compositions for inhibiting antigen-induced respiratory anaphylaxis comprising a non-toxic effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a histamine receptor antagonist and an acceptable pharmaceutically acceptable carrier or diluent.

This invention also relates to the method of treating diseases in which leukotrienes are a factor in a subject in need thereof which comprises administering to such subject an effective, non-toxic amount of one of the compositions pharmaceutical compositions described above.

This invention also relates to the process for the preparation of; compounds of Formula (I) of known chirality, characterized by a) reacting an appropriate diester with a strong bass to produce an intermediate thiol, and b) reacting the thiol with an alkylating agent or a Michael acceptor, ie, a unsaturated carbonyl compound, to give a compound of Formula (1).

Detailed Description of the Invention

These compounds of the invention are those represented by the formula-preparation process. structural (I)

wherein q is 0, 1 or 25

R 1 is (L) a - (CH 2) b - (a) M a is 0 or 11 b

CIP is 0 or 1; L and T are; sulfur, oxygen or CH 2 with

which L and 1 does not contain C1-4, e: 611, O, cyclohexy by Sr 7 Cl CF

C1-4 alkoxy

methylthio or trifluoromethylthio; 9.2 and A are independently selected from H, CF3, C1-4 alkoxy, C1-4 alkoxy, F, Cl, Br, I, OH, M02 or MH2s, or those of R1A are H, then R2 may be as defined above), wherein a, b, 0, L, 6 and H are defined as: or (CH 2) p -Z wherein R 3 is OH, MH 2, aryloxy or alkoxy is 0 or 1 and p is 0, 1 or 2, -4. C1-4 alkoxy or F | COR z or tetrazolyl

; &quot; W &quot; point when d is not 0; and are each hydrogen or C 1-4 -alkyl in any W is a six-membered aryl or heteroaryl ring, selected from phenyl, pyridyl or pyrimidyl, unsubstituted or substituted by one or more of 3, C or D , or W is a C 15 -C 71 102 Cc Case 14343-CIP 1

in which R 5 and R 6, s is p is 0 to 63 each, hydrogen or C 1-4 alkyl is H 5 C 1-4 alkyl, COR 3, SO 3 H, SO 2 H, S 2 NH 2, C 2 H 2 OH 5, or tetrazolyl O 2 with R 3 defined as

from H, C1-6 alkylthio, C1-C4 alkyl and C1-4 alkyl-C and D are independently selected, OH, F, Cl, Er, CF3, alkoxy trifluoromethylthio, NO2, NH C1-4 alkyl or a pharmaceutically acceptable salt thereof.

A particular class of compounds of this invention are those represented by structural formula (II)

D.

in which R * f, ^ 2? above. O 1- 115; are defined with those

A subgeneric class of these compounds are represented by the structural formula (III): ## STR1 ## Λ III J · "in which act.

C B (III) x x is represented by formula

A particular group of the subgeneric class of formula (1) are the structural (III)

(III G Λ

wherein X is DH, OH or OCH3 I is 0 or 1; s

Rj_; &amp; 2p A and C are as defined above.

The compounds of the formulas (III) and (IIIA) are exemplified by the following compounds (1) 2-hydroxy-3- (2-carboxyphenylthio) -3- [2- (8-phenyl-octyl) phenyl] propionic acid; (2) 2 (S) -hydroxy-3 (R) - (2-carboxyphenylmethylthio) -3- [2- (S Phenyl) c] ο ϊ (3) 2 (S) -hydroxy-3 (R) - (3-carboxynylmethylthio) -3- [2- (8-phenyloctyl) phenyl] propionic acid; (4) 2-hydroxy-3- (3-carboxyphenylthio) -3- [2- (8-phenyl-

(5) 2-hydroxy-3- (4-carboxyphenylthio) -3- [2- (S-phenyl-octyl) phenyl] propionic acid; (6) 2-hydroxy-3- (4-carboxy-2-methoxyphenylmethyl) -3- [2- (S -phenyloctyl) phenyl] propionic acid; and (7) 2-hydroxy-3- (4-carboxyphenylmethylthio) -3- [2- (S -phenyloctyl) phenyl] propionic acid; (8) 2-hydroxy-3- (2-fluoro-4-carboxyphenylmethylthio) -3- [2- (S -phenyloctyl) phenyl] propionic acid; (9) 2-methoxy-3- (4-carboxyphenylthio) -3- [2- (8-phenyl-octyl) phenyl] propionic acid; (10) 2-hydroxy-3- (4-hydroxyphenyl) -3- [2- (8-phenylpiperazino) propionic acid; and (11) 2-methoxy-3- [4-carboxy-2-ethoxyethoxyphenylthio) -3 "- [2" (8-phenyloctyl) phenyl] propionic acid.

The second subgeneric class of compounds of formula (II) are those represented by structural formula (IV)

(IV) wherein R 1, R 2, A, B, C, D, q and d are as defined above and p is 1 or 2.

The compounds of formula (IV) are exsipped by the following compounds: (1) 3- (2-Carboxyphenylthio) -3- [2- (8-phenyloctyl) phenyl] propionic acid 3- (2- carboxyphenylmethylthio) -3- [2- (8-phenyloctyl) -8- SBC Case 14343-ΌΪΡ v Π Π 1 * * * ó ó ó ó ó ó ó ó ó ó ó ó ó ó (3) 3- (4 "carboxy-2-phythoxyphenylmethylthio) -3- [2" (8-phenylethyl) phenyl] propionic acid.

A third subgeneric class of the compounds of formula (II) are those represented by structural formula (V);

Wherein d and q are defined as above *

The compounds of formula (V) are exemplified by the following compounds: (1) 2- (2-carboxyphenylthio) -2- [2- (8-phenyloctyl) phenyl] 2- (2-carboxyphenylmethylthio) -2- [2- (8-phenyloctyl) phenyl] acetic acid 2- (2-carboxyphenylmethylthio) -2- [Î ± - (8-phenyloctyl) -ketoacetic acid. • Private class, add. compounds of this invention are those represented by structural formula (VI)

(I.e.

71 102 mc Case 14343-ϋϊΡ 1 -19-ββϊ que that Rj j $ 2? Y, R 5, R 4, q and d are as defined for formula (1),

Compounds of formula (VI) are exemplified by the following compounds: (1) 2-hydroxy-3- (2-carboxy-4-pyridyl) -3- [2- (S-phenoxyethyl) phenyl] propionic acid (2) 3- (2-Carboxy-4-pyridylthio) -3- [2- (N -silyloxyethyl) phenyl] propionic acid; and (3) 2- (3-carboxy-4-pyridylmethyl) -2- [2- (8-phenyl-octyl) phenyl] acetic acid,

A further particular class of compounds of this invention are those represented by structural formula (VII)

Did you laugh, Ro? R5, R &amp; Y, q and d are as defined above,

The compounds of formula (VII) are exemplified by the following compounds: (1) 2-hydroxy-3- (2-carboxy-4-pyrimidylthio) -3- [2- (8-phenyloctyl) (2) 3- (2-carboxy-4-pyrimidylthio) -3- [2- (S -phenyl-ethyl) -pyrimidopropyl] -piperidine-2-carboxylic acid 4-pyrimidyl-methylthio) -2- [2- (S-phenylsulfinyl) phenyl] acetic acid.

The compounds of the present invention which contain one or two carboxylic acid groups are capable of forming salts with pharmaceutically acceptable bases according to procedures well known in the art. Such acceptable bases include inorganic organic bases, such as ammonia, arginine, organic amines, alkaline earth and alkali metal bases. Of particular utility are the potassium, sodium, ammonium, magnesium and calcium salts,

Some of the compounds of formula (I) contain one or two asymmetric centers. This leads to the possibility of two or four stereoisomers for each of these compounds. The present invention includes all such stereoisomers, racemates or the like.

The compounds of the formula (I) wherein Y is COOH are conveniently prepared from an alkyldione precursor of the following formula (VIII)

(VIII) wherein R1 and R2 are described above. A compound of formula (VIU) is treated with trimethylsilyl cyanide in the presence of zinc iodide at low temperatures in an inert solvent to form the trimethylsilyl protected cyanohydrin, treatment with hydrogen chloride gas in methanol, provided the methyl 2-hydroxyacetate derivative, which is converted to the 2-chloroacetate with thionyl chloride. This valuable intermediate is then reacted with a selected substituted thiol to give, after removal of the ester proton groups, a product of formula (I).

71 102 SBC Case 14343-CIP 1 -21-

The compounds of formula (I) wherein γ is or CH (X) Co 2 H wherein X is H, C 1-4 alkyl or C 1-4 alkoxy are prepared by reaction of the appropriate aldehyde of formula (VI) and a bromoacetate -amide is conveniently provided with a mixture of diethyl aluminum chloride, zinc powder and a catalytic amount of cuprous bromide at low temperatures in an inert solvent to give the 3-hydroxypropionate derivative. which reaction mixture is reacted with a substituted fciol in trifluoroacetic acid. Alternatively, a mixture of trimethyl borate and zinc in tetrahydrofuran may be used to prepare the 3-hydroxypropionate derivative. Alternatively, an aldehyde of formula (VIII) may be reacted at low temperature with the lithium salt of a esterified acetic acid, suitably t-butyl acetate, in an inert solvent, to give the 3-hydroxypropionate derivative The compounds of formula (I) wherein Y is O.CH (CH 3) CO 2 H are obtained by use in the above reaction of a β-bromopropionate esterified with an aldehyde (VIII).

To prepare the compounds of formula (I) wherein q is 1 or 2, the appropriate thio product is conveniently oxidized with sodium periodate or meta-chloroperbenzoic acid to provide the sulfoxide or sulfone product.

Alternatively, compounds of formula (I) wherein Y is wherein X is H, C 1-4 alkyl, C 1-4 alkoxy or fluoro are prepared from a propynoate precursor of the following formula (IX)

(IX) wherein R 1 and R 2 are as described above, R 1 is a standard ester protecting group such as t -butyl and R 1 is H, C 1-4 alkyl, C 1-4 alkoxy or fluoro. A compound of formula (IX) is reacted with an alkali metal alkoxide mixture, such as sodium methoxide, and substituted thiol to give, after removal of the group

Ester protecting group, products of formula (I),

The propenoate precursors of formula (IX) are prepared from the corresponding aldehydes of formula (VIU) by general procedures such as an alkyl (triphenylphosphorinylidene) acetate acetate reaction or by converting the aldehyde to a 3-hydroxypropionate derivative , described as above, followed by a deletion reaction to form &amp; double bond. Further, the propenoate precursor is obtained, from a 3-methanesulfonyloxypropionate derivative, by treatment with triethylamine.

The compounds of formula (I) wherein Y is CH (OH) (CH2) p CO2 are prepared from an epoxide precursor of the following formula (X)

wherein R2, fi and p are described above and is a lower alkyl, such as methyl or ethyl. A compound of the formula (&gt; ') is reacted in an aprotic solvent with triethylamine and a substituted thiol selected to give, after removal of the ester protecting groups, a product of formula (I).

The epoxide precursors of formula (X) wherein p is 2, are prepared by reacting the Srignard derivative of a bromobenzene compound of formula (Xi)

(XI)

A with acrolein, to give the corresponding enol derivative which is treated with a trialkyl orthoacetate, followed by epoxidation using m-chloroperbenzoic acid * 71 102 BBC Case 14343-ClP 1

and they are

The precursors of the compounds of the formula (X) are an aldehyde of the formula (VIII), or an alkoxide with a metal

The compounds of formula (I) were prepared from an ester of formula (I) and the compounds of formula (I) were prepared from an ester of formula (I). is CH (CM2) pCOOH may OH of the formula structure 1

(CH 2) bc ° 2r 7 CD 2 R 8 (ΧΙΪ) wherein R 7 and R 9 are the same, or differing from each other. A compound of formula (XII) is alkyl with hydrido and cyclopropyl. sodium chloride in an inert solvent followed by reaction with a substituted benzyl bromide to give a desired product. The compound of formula (I) wherein Y is (CH 2) 3 CO 2 H are prepared from a tetrahydro-4 H -pyran-2-one precursor of the following formula (XIII )

(XIII) wherein Rj &amp; triethylamine and triethylamine are reacted with a mixture in an inert solvent, trifluoroacetic acid to give, A compound of formula (X) of zinc iodide and one or with a substituted thiol of any of the groups III) thiol in an ester group, a product of formula (I) = Case 14343-CIP 1 -24-

The precursors tetrahydro-4H-p-n-2-yl) of formula (I-3) are prepared by reacting the 1α-Mn derivative of the bromobenzene compound of formula (XI) with the tri chloro & followed by reaction with the &gt; -oxo ester. I rent from

The aldehydes of formula (VIII) are known or readily prepared using the procedures as described below. sscr i

3 X

The aldehyde precursors of the compounds of the fork R j are, for example, an alkyl radical containing a compound (I) in the a-13 carbon atoms are prepared from the appropriate 2-a] oxyphenyl-4,4-dimethyl-oxazoline [see Meyers et al., J. Org. (1978)]. 137 '

The aldehyde precursors of the compounds of the formula (I) wherein R1 is, for example, an alkoxy radical containing 7 to 12 carbon atoms are prepared by the 0-alkylation of 2-hydroxybenzaldehyde. of the appropriate amount with the corresponding alkylating agent.

The aldehyde precursors of the compounds of Formula (I) wherein R 1 is an alkynyl containing 1 to 12 carbon atoms are prepared by coupling a 2-halobenzaldehyde with the appropriate 1-alkyne in the presence of iodo-cuprous The catalytic hydrogenation of these alkynyl containing precursors under standard conditions affords the aldehyde precursors of the compounds of the formula (## STR1 ## in which R 1, I) wherein it is an alkyl or phenyl radical

Exemplary alkylene precursors of the compounds of formula (I) are prepared by the appropriately substituted benzene, dimethylacetamide. of the haloalkyl group, a thiophenol, and the like.

Aldehyde precursors containing compounds of formula (1) are prepared by the appropriately substituted alkylbenzaldehyde with triethylamine.

71 102 SBC Case 14343-ClP 1 -25-

The heteroarylmercaptan precursors required to prepare the compounds of formula (I) are known compounds and are conveniently prepared by the use of common chemical reactions. The mercapto derivatives of these precursors are prepared according to the known methods. These mercaptans are reacted as described above to give compounds of formula (I),

Appropriate modifications of the general processes described, and as the posterly described in the Examples provided below, provide the various compounds defined by formula (1),

This invention further relates to the process for the preparation of the compounds of Formula (I) of known chirality, characterized in that the reaction of a diester with a strong base to produce a thiol is then reacted with an alkoxide agent or Michael acceptor to give the desired compound,

A suitable diester is represented by Formula (XIV)

13 f γτν \ ha where d is 2; X3 OH? one of R 5 or R 4 adjacent to the ester group is H and the other is H or C 1-4 alkyl and F 1, R 2, A 3, sp are defined as in Formula (I) and R 2 and R 13 are selected independently from alkyl. Suitable strong bases include those such as sodium methoxide, sodium hydride, sodium arnide, lithium diisopropylamide or the like. The reaction is conducted in an aprotic solvent such as tetrahydrofuran, dimethylsulfoxide or N, N- dimethylformamide, SSC Case 14343-C1P1 at room temperature and pressure. The resulting thiol intermediate of known chirality is represented by Formula (XV)

in which R 1, R 2, R 13, A, X and p are as defined in Formula (XIV). The thiol of Formula (XV) is reacted with an alkylating agent or acylating agent to give a compound of Formula (Ϊ). Suitable alkylating agents include alkyl halides such as alkyl bromide or alkyl iodide. Benzyl halides are especially suitable for preparing compounds of Formula (I). The reaction is run in a solvent at approximately room temperature and pressure. Suitable Hichael acceptors include those compounds which undergo nucleophilic addition. Examples include compounds containing carbonyl, carboalkoxy or cyano groups conjugated to a double or triple bond. The carbonyl compounds or the alleles represented by the following structural formulas are especially suitable for the preparation of the compounds of formula (I): wherein R1, R2, R3 and R4 are independently selected from from hydrogen or C1-6 alkyl. R 15 and R 17 are independently selected from H, aryl or alkyl. The reaction is conducted in a solvent at approximately room temperature and pressure. The leukotriene antagonist activity of the compounds of this invention is measured by the ability of the compounds to inhibit leukotriene-induced contraction of the in vitro guinea pig 27-71 102 SBC Case 14343-CIP tracheal tissues in vitro. The following methodology was employed

In vitro: guinea pig tracheal spiral strips (male albino male of the Hartley strain) of approximately dimensions were washed! 2 to 3 mm cross-sectional width 3,5 3.5 cm in length, in modified Krebs buffer, in 10 ml tissue bath, jacketed, and then air-washed with O 2 at 95 æC / 2. to 5¾. The tissues were attached via a silk suture to displacement-force transductorss for isometric voltage recording. The tissues were equilibrated for 1 b, pretreated for 15 minutes with meclofanamic acid (IpJM) to remove intrinsic prostaglandin responses and then pretreated for a further 30 minutes with either the test compound or the control vehicle . A cumulative concentration-response curve for the LTD4 in triplicate tissues was produced by successive increases in the LTD4 concentration in the bath. In order to minimize intertussive variability, contractions caused by LTD4 were normalized as a percentage of maximal response obtained with a reference agonist, carbachol (10wM). Calculations The means of the response curves at three-fold concentrations of LTD4 either in the presence or absence of the test compound were plotted on legarithmic paper. The concentration of LTD4 required to cause 30% of the contraction caused by carbachol was measured and defined as the EC3 0 = -log! Value for the test compound was determined by the following equations: 1. EC3 O (in the presence of compound of test) = dose ratio = X EC30 (in the presence of control vehicle) 7. kg * test compound concentration / (XI)

The compounds of this invention possess a bio-enhancing antagonistic activity against the lupus, especially leukotriene D4. The antagonist activity of representative compounds of this invention is reported in Table I. The values of -log kg were calculated from the above protocol. Where corisipostos were tested more than once

values of the data given here represent the actual medical values.

Table I

The Leukotriene Antagonist Activity of the compounds of Formula (III) is known as R2, h7 C and o without, q -s. ρ is 0, Z is COOH and R 1 is γ-fenzloctyl. C = N-N-diisopropylcarboxamide; 0 2 "d02" "OH 5,5 -> 1 2 -CH 2 OH OH 5.2 1. 3 "C021H OH 5.6 &gt; 0 3-COOH GH 7.0 * T ** υ 4-COOH OH 7.6 - / * 1 2-CCH 3, 4-COOH OH * "7 ^, 5 '' 7 ^ C02K OH &quot; T -: w &gt; 1 2-F, 4-C02H GH 7.8 J-4-COO-H -CH 2 CH 2 -CH 2 CH 2 Gt; 4-COO-2-GCH3 BJ! The pharmaceutical compositions of the present invention comprise a pharmaceutical composition or amount of urea in the amount of the compound of formula (I). (Ϊ) or a pharmaceutically acceptable salt thereof, such as an alkali metal salt thereof, is prepared by reacting the compound of formula (I) with a pharmaceutically acceptable salt thereof. inhibition of the effects of leuuriaires, such as asthmatics and other hypersensitivity diseases.

Where the pharmaceutical composition is empirical in the form of a seduction or suspension, examples of carriers or diluents

71 102 SBC House 14343-CIP 1 Suitable pharmaceuticals include: for aqueous systems, water; for non-aqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid paraffins and mixtures thereof with water? for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluorostane and compressed carbon dioxide. In addition to the pharmaceutical carrier or diluent, the present compositions may also include other ingredients such as stabilizers, anti-oxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, as long as the additional ingredients do not have a detrimental effect on the therapeutic action of the present compositions. The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend on the desired route of administration, i.e., parenterally, topically or by inhalation.

In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus, the compositions will comprise a suspension or solution of the active ingredient in water, for administration by means of a conventional nebulizer. Alternatively, the compositions will comprise a suspension of the active ingredient solution in a conventional liquid propellant or in a compressed gas to be delivered from a pressurized asrosol vessel. The compositions may also comprise the solid active ingredient diluted with a solid diluent for administration from a powder inhalation device. Preferably, the amount of carrier or diluent will vary, but will preferably be greater proportion of a suspension or solution of the active ingredient. Where the diluent is a solid, it may be present in amounts less than, equal to or greater than those of the solid active ingredient.

As a parenteral administration the pharmaceutical composition will be in the form of a sterile injectable solution or an aqueous or non-aqueous liquid suspension. • 30-71 102 SBC Case 14343-CIP 1

For topical administration the pharmaceutical composition will be in the form of a cream or ointment.

Typically, a compound of formula (I) is administered to an animal subject in a composition comprising a non-toxic amount sufficient to produce an inhibition of the symptoms of an allergic response. When employed in this manner, the dosage of the composition is selected from the range of 350 mg to 700 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 2 times a day, the daily dosage regimen being selected from about 350 mg to about 2800 mg. The pharmaceutical preparations thus described are prepared following conventional pharmaceutical chemistry techniques suitable for the desired end product.

Included within the scope of this disclosure is the method of inhibiting the symptoms of an allergic response resulting from the delivery of a mediator comprising administering to an animal subject a therapeutically effective amount for the production of said inhibition of a compound of formula (I), preferably in the form of a pharmaceutical composition. The admixture may be carried out in dosage units, at appropriate intervals, or in single doses as required. Usually, this process will be practiced when the relief of allergic symptoms is required. However the process is also usefully performed as a continuous or prophylactic treatment. It is within the scope of the art to determine, by routine experimentation, the effective dosage to be administered, from the dosage range described above, taking into account factors such as the degree of severity of the allergic condition to be treated, etc.

The compounds of this invention alone and in combination with a histamine receptor antagonist inhibit antigen-induced contraction of the isolated and sensitized trachea of cankers, (a model of respiratory anaphylaxis). Examples of histamine 1 receptor antagonists are mepyramine, chlorpheniramine and 2- [4- (5-bromo-3-methylpyrid-2-yl) butylamino] - 5 - [(6-methylpyrid-3-yl) methyl] -4-pyrimidone, and other known receptor antagonists.

As described herein, the pharmaceutical compositions of the present invention also comprise a pharmaceutical carrier or diluent and a combination of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, a histamine H 2 receptor antagonist, in amounts sufficient to inhibit the antigen-induced respiratory anaphylaxis. To this end, the above-defined dosage of the compound of formula (I) and the known effective dosage for the histamine H receptor antagonist are desirably used for this purpose. The methods of administration described above for a single active ingredient may, similarly , a combination of a histamine H1-

The following examples illustrate the preparation of the compounds of this invention and their incorporation into pharmaceutical compositions and, as such, are not to be construed as limiting the invention described in the appended claims. EXAMPLE 1

Preparation of 2-hydroxy-3- (2-carboxyphenylphenoxy) -5- [2- (3-phenyloctyl) phenylpropionic acid (a) 2- (8-phenyloctyl) benzaldehyde

A solution of 8-phenylethanoic acid (19.8 mmol) in dry tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 0 ° C for 4 hours to give or 3-phenyloctanol. To an ice cold solution of octanol (ca. 19.0 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was dissolved in ether (100 ml), chilled on ice. The filtrate was evaporated and distilled to give the bromide of the title compound as an oil. To 8-phenylethylmagnesium bromide (from 24.25 mmol of 8-phenylethyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 mL) was added 2- (2-methoxyphenyl) -N- 4,4-dimethyloxazoline (17.10 mmol) [Al Meyers et al., J. Org. Chem., 45, 1372 (1978)] in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was worked up to give 2- [2- (8- -phenyloctyl) phenyl] -4,4-dimethoxyazoline, as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 mL) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide, as a white solid (p.1L, 76.5-732C). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 mL) was added portionwise sodium borohydride (9.20 mmol). The reaction mixture was stirred for 30 minutes, and then the reaction was quenched with 5 percent sodium hydroxide (50 ml). The reaction mixture was extracted with ethyl ether (2 x 50 ml) and the extract was washed with brine (50 ml) and dried over anhydrous magnesium sulfate. The evaporation of the filtrate gave an oil which was dissolved in acetone (50 ml ) and 3N hydrochloric acid (10 ml) was added. The mixture was stripped with argon and stirred for 16 hours at room temperature. The volatiles were removed in vacuo and the residue partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous phase was extracted with more diethyl ether (50 ml). The combined organic phase was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. Evaporation of the organic phase gave an oil which was purified by flash chromatography on silica gel with 2% ethyl acetate in hexane as eluant to provide the desired product as a colorless oil.

Analysis for C₂ ^H₂ 26N₂O: Calculated: C, 35.67; N, 3.90. Found: C: 85.12, 85.22; H, 8.94, 8.96, (b) Alternative preparation of 2- (S-butyloctyl) benzaldehyde A solution of 5-hexynyl alcohol (102 mmol) in pyridine 71 102 SBC Case 14343-CIP14

(150 ml) under argon was cooled to 0 ° C and p-toluenesulfonyl chloride (204 mg) was added. The reaction mixture was maintained at about 42 ° C for 18 hours, cooled to ice water and then dissolved in ether. The ethereal extract was washed with cold 10% hydrochloric acid, water, and brine. The organic layer was dried and concentrated in vacuo to give 5-hexynyl p-toluenesulfonate. A solution of phenylacetylene (97 mmol) in tetrahydrofuran (200 ml), counting a trace of the trienylmethanone was cooled, (37.3 mL, 2.6 mol in hexane). The resulting solution was stirred at 0 ° C for 10 minutes and hexamethylphosphoramide (21 mL) was added. ) dropwise. After stirring for 10 minutes, a solution of 5-hexynyl p-toluenesulfonate in tetrahydrofuran (97.1 mmol) (200 mL) was added. The reaction mixture was stirred at room temperature for 13 hours, diluted with ether and the organic layer was washed with water and brine, the dried organic solution was concentrated and the product was purified by flash chromatography to give 1-phenylocta- 7-di-nino. A mixture of this compound (43 mmol), 2-bromo-2-aldodehyde (35.8 mmol), euprous iodide (0.5 mmol) and bis (triphenylphosphine) in triethylamine (100 ml) was heated in an oil bath (95 DEG C.) for an ivy. The reaction mixture was cooled to 0 ° C, filtered and the filtrate was concentrated. The residue was dissolved in ether, washed with 10% hydrochloric acid, water and brine. The organic layer was dried and concentrated to give a product which was purified by flash chromatography to give 2- (S-phenyl- A solution of this compound (24.1 mmol) in acetic acid (100 mL) and 10% palladium on charcoal (1 g) was hydrogenated (40 psi hydrogen) at room temperature for 7 hours. The catalyst was filtered and the filtrate concentrated to give 2- (8-phenyloctyl) benzaldehyde. (C) Trans-5- [2- (8-phenyloctyl) phenyl] -2,5-epoxypropionate of Example 1 (a) or (b) (2.94 g, 10 mmol) was dissolved in diethyl ether (25 ml) and the solution was stirred under nitrogen.

(1.32 mL, 15 mmol) was added, followed by the addition of sodium methoxide (810 μg, 15 mmol), followed by addition of sodium methoxide (810 μg, 15 mmol) The mixture was stirred for 2.5 hours at ice-bath temperature. A small amount of water, the separated ethereal phase, dried over anhydrous sodium sulfate, filtered and evaporated. Flash chromatography of the residue on 50 grams of silica gel eluted with 5-30% ethyl acetate / hexane to give the product. (d) Methyl 2-hydroxy-5- (2-carboxyphenylthio) -5- [2- (3-phenyloctyl) phenyl] propionate

A solution of the compound of Example 1 (e) (0.51 g, 1.39 mmol), 2-methylaptobenzoic acid (0.24 g, 1.53 mmol) and triethylamine (0.31 g, 3.06 mmol) in 10 ml of methanol was stirred overnight at 22 ° C under argon. The mixture was poured into water, acidified with 1M hydrochloric acid and extracted with diethyl ether. The extracts were dried and the solvent evaporated. The residue was flash chromatographed on silica gel to remove starting materials and the product eluted with a mixture of ethyl acetate, hexane and methanol (60: 40: 2.5). The solvents were evaporated and the residue was recrystallised from methanol to give the product, 230 mg (32%). (s) 2-Hydroxy-5- (2-carboxyphenyl) -3- [2- (8-phenyl-octyl) phenyl] propionic acid

A suspension of the compound of Example 1 (d) (0.23 g, 0.44 mmol), 5 mL of methanol, 2 mL of water and 2 mL of 2.5 N sodium hydroxide was heated at 95 ° C for 10 minutes and stirred at 22 ° for 2 h. The mixture was diluted with 20 ml of water and filtered. The filtrate was acidified and extracted with ethyl acetate. The extracts were washed with water, dried and the solvent evaporated. The residue was recrystallized from acetonitrile and gave the desired product, 182 mg (82%). PMM (CDCl 3 / Me 2 CO) 9.70 ppm (broad s, 3H), 7.05-8.06 (m, 13H), 5.28 (d, 1H), 4.76 (d, 1H) 4Q-3, C5 (m, 4H), 1.13-1.72 (m, 12H).

71 102 SBC Case 14343-CIP 1 -35

Similarly, the following compounds are prepared according to the general procedure of Example 1 from 2- (2-methoxyphenyl) -4,4-dimethyloxazoline and the appropriate alkyl halide 2-hydroxy-3- ( 2-carboxyphenylthio) -3- [2- (3-phenylpropyl) phenyl] propionic acid; 2-hydroxy-3- (2-carboxyphenylthio) -3- [2- (14-phenylpropyl) cyclo] phenyl] propionic acid; 2-hydroxy-3- (2-carboxyphenylthio) -3- (2-butylphenyl) propanoic acid 2-hydroxy-3- (2-carboxyphenylthio) -3- (2-dodecylphenyl) propionic acid; and 2-hydroxy-3- (2-carboxyphenylthio) -3- (2-octadecyl) propionic acid. EXAMPLE 2

Preparation of 2 (S) -hydroxy-5 (R) - (2-carboxyphenylmethylthio) -3- [2- (3-fluoroethyl) phenyl] propionic acid (a) 3- (2-carbomethoxyethylthio) -3- Methyl ester The compound of Example 1 (c) (1.2 g, 3.28 mmol) was dissolved in methanol (20 ml) containing 2% triethylamine and stirred under argon at room temperature. The methyl 3-mercaptopropionate (0.623 mL, 5.45 mmol) and triethylamine (1.45 mL, 9.84 mmol) were dissolved in methanol (15 mL) and added dropwise. The mixture was stirred for 18 hours. The solvent was separated and the residue eluted with 20% ethyl acetate / hexane to give a mixture of the desired product and its regioisomer, 2- (2-carbomethoxyethylthio) -3- [2- (8-phenyloctyl) phenyl] - 3-hydroxypropionate. The mixture was rematomatographed on 100 g of neutral alumina, to remove the desired product.

(B) Grito-3- (2-carboxyethylthio) -3- [2- (8-phenyloctyl) phenoxy] -2-hydroxypropanoic acid The desired product of Example 2 a) (320 mg, 0.66 mmol) was dissolved in methanol (10 ml) and stirred under argon at ice bath temperature. 1N sodium hydroxide solution (2.5 mL, 2.5 mmoles) was added dropwise, the ice bath removed, the mixture stirred at room temperature for 2.5 hours, and then, After cooling for an additional hour at room temperature, methanol was removed, the residue diluted with water was adjusted to pH 3.5 with dilute hydrochloric acid. Removal with ethyl acetate followed by drying over sodium sulfate The crude product which was flash chromatographed on silica gel pellets, eluted with ethyl acetate: hexane: formic acid at 30:70 = 0.5 to give the free acid product, (e) The racemic dihydrochloride of Example 2 (b) (63.5 g, 0.138 mol) in 700 ml of isopropanol was cooled to 0 ° C , was treated with a solution of (R) -4-bromo-β-phenethylamine (57.1 g, 0.286 mole) in 200 ml of isopropanol at 25 ° C. The resulting solution was stirred for 3 hours, causing the crystallization of the 2S, 3R diamine salt. The suspension was cooled to 5Â ° C, filtered and the salt recrystallized twice from ethanol to give 37.7 g (72%) of the salt of the 2S, 3R diamine, m.p. 146-147Â ° C; [Î ±] 24 C = -45.8Â ° (C = 1, CH3 OH). The diamine salt (37.7 g, 0.0497 mol) was added in p-oestrals to 400 ml of cold 0.5N aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the ethyl acetate solution washed three times with 0.5N hydrochloric acid. The ethyl acetate solution was washed with brine, dried and concentrated to give 19.5 g (97%) of 2 (S) -hydroxy-3 (R) - (2-carboxystilthio) -3- Desired [2- (S-phenyloctyl) -phenyl] propionic acid; [Î ±] 242_40.82 (C = 1, CHCl3). 71 102 SBC C3.53 14343-CIP 1 -37-

(d) Methyl 2 (S) -hydroxy-3 (R) - (2-carbomethoxyphenylthio) -5- (2- (8-phenylethyl) phenyl] propionate

A solution of 2 (8) -hydroxy-3 (R) - (2-carboxyethylthio) -3- [2- (8-phenyloctyl) phenyl] propionic acid (1.0 g, 2.18 mmole) in 100 ml of (2-carbomethoxysulfinyl) -3- [2- (S) -hydroxy-3 (R) - (2-carbomethoxysulfinyl) (S -phenyloctyl) phenylpropionate, 1.06 g (100%). (e) methyl 2- (S) -hydroxy-3 (R) - (carbomethoxyphenylmethylthio) -5- (2- (S -phenyloctyl) phenylpropionate

A solution of the compound of Example 2 (d) (675 mg, 1.39 mmol) in 12 ml of tetrahydrofuran and 4 ml of N, N-dimethylformamide at 0 ° C was treated with sodium hydride (2 , 92 mmol). After 30 minutes, 2-carbomethoxybenzyl bromide (350 mg, 1.53 mmol) was added and the mixture was stirred at 22Â ° C for 2 hours and at 60Â ° C for 2 hours. After cooling, the mixture was diluted with water, acidified and extracted with ethyl acetate. The extracts were dried and the solvent evaporated. The residue was first chromatographed on silica gel with ethyl acetate / hexane (3: 7) as eluent, then on an alumina column with ethyl acetate / hexane / methanol (75: 25: 1) as the eluent, the product was isolated as an oil, 230 mg, (f) 2 (S) -hydroxy-5 (R) - (5-carhoxyphenylmethylthio) -5- [2- (S -phenyloctyl) phenyl] propionic acid

A solution of the compound of Example 2 (e) (130 mg, 0.24 mmol) in 2 mL of methanol was treated with 2 mL of 2.5 M sodium hydroxide, heated at 80 DEG for 10 minutes. The solution was diluted with 10 ml of water, filtered, the acidified filtrate to be extracted with ethyl acetate. The extracts were washed with water, dried and the solvent removed to give the product as an oil, 97 mg (73%). NMR (CDCl 3 / Me 2 CO) 8.05 ppm (d, 1H), 7.67 (m, 1H), 6.96-

71 102 mc Case 14343-ClP 1 EXAMPLE 3

Preparation of 2 (S) -hydroxy-3 (R) - (5-carhoxysulfonylthioethyl) -3- [2- (S -phenyloctyl) phenylpropionic acid (a) 2 (S) -hydroxy-5 (R) - (5-carboethoxy) ) Methyl 5-2- (2- (5-phenyloctyl) phenyl) propionate

A solution of the compound of Example 2 (d) (370 g, 0.76 mmol) in 10 ml of tetrahydrofuran and 5 ml of N, N-dimethylformamide was first treated with sodium hydride (1.53 mmol ), followed by 2-carboethoxybenzyl bromide (203 mg, 0.84 mmol). The mixture was stirred at 22 ° for 1 h, poured into 100 ml. 1N hydrochloric acid, cold, and, extracted with diethyl ether. The extracts were washed with water, dried and the drying agent filtered, the filtrate was treated with an ethereal solution of diazomethane for 30 minutes at 222, then evaporated. The residue was initially chromatographed on alumina with ethyl acetate / hexane / methanol (80: 20: 5) as eluent, then on silica gel with ethyl acetate / hexane (3: 7) as eluent. The product was isolated as an oil, 170 mg (41%). (b) 2- (8) -hydroxy-5 (R) - (3-carboxyphenylmethyl) -3- [2- (8-phenyloctyl) phenyl] propionic acid

A solution of the compound of Example 3 (a) (170 mg, 0.30 mmol) in 5 mL of ethanol was treated with 4 mL of 5% sodium hydroxide and the mixture heated under argon at 65 ° for 1 hour. was diluted with 10 ml of water, treated with activated charcoal and filtered. The filtrate was acidified and extracted with chloroform. The extracts were washed with water, dried and the solvent evaporated, yielding the product as an oil, 137 mg (87%). NMR (CDCl3): 7.0-9.0 (m, overlapping broad s, 16apos;), 4.69 (s, 1H). 1H), 4.48 (d, 1H), 3.80 (d, 1H), 3.64 (d, 3H), 2.18-2.70 (m, 4H), 1.0-1.70 (m, 121-1) c 71 102 8BC Case 14343-CIP 1

EXAMPLE 4 Reaction of 2-hydroxy-5- (5-carboxyphenylphenoxy) -5- (2- (8-phenyloxy) phenyl) propionic acid (a) 2-hydroxy-5- 5-carboxyphenylthio) -5- [2- (8-phenyloctyl) phenyl] propionate To the solution of the compound of Example 1 (c) (525 mg, 1.43 mmol) was added to m-mercaptobenzoic acid (331 mg, , 15 mmol), prepared according to Wiley, PF, J. Org. Chem., 16, 812 (1951), in a mixture of 4 ml of methanol and 0.5 ml of triethylamine, was stirred at 232 ° C for 16 hours. The actual mixture was poured into 0.5M HCl and EtOAc. with ethyl acetate. The extracts were dried, evaporated and the residue, chromatographed on silica gel, the product together with the regioisomeric compound, was eluted with ethyl acetate. The solvent was evaporated, the residue dissolved in 10 ml of methanol, treated with 1 ml of 25% NaOMe in methanol, and stirred at 232 ° C for 4 hours. The mixture was diluted with 0.5 M HCl and extracted with ethyl acetate , And the extracts were dried, evaporated and the residue chromatographed on silica gel, the product eluted with a mixture of ethyl acetate, hexane, methanol and acetic acid (75: 25: 5: 1) and gave, after evaporation of the solvents , 185 mg (25%), (b) 2-Hydroxy-3- (5-carboxyphenylthio) -5- [2- (8-phenyl-octyl) phenyl] propionic acid

A solution of the compound of Example 4 (a) (144 mg, 0.28 mmol) in 5 mL of ethanol was treated with 2 mL of 0.5 N WaOH and stirred at 232 ° C for 2 hours. ml water, filtered, the filtrate acidified and extracted with ethyl acetate. The extracts were dried and evaporated to give the title product, 105 mg (75%) NMR (CDCl3 / MS2CO): 8.22 (s, 1H), 6.70-8.10 (m, 15S). 5.02 (d, J = 4.3 Hz, 1H), 4.64 (d, J = 4.3 Hz, 1H), 2.42-2.26 (m, 4H) 74 (m, 12H). 71 102 SBC Case 14343-CIP 1

EXAMPLE 5

Preparation of 2-hydroxy-3- (4-carbaxifenylthio) -3- [2- (8-phenyloctyl) phenyl] propionic acid

The mixture of the compound of Example 1 (e) (644 mg, 1.76 mmol) and p-mercaptobenzoic acid (325 mg, 2.11 mmol), prepared in a similar manner to the meta analog of Example 4 ) in 10 ml of methanol and 0.6 ml of triethylamine was stirred at 232 ° C for 16 hours. The solution was treated with 1 ml of 25% WfOMe in methanol, stirred for 3 hours, poured into 0.5 M hydrochloric acid and extracted with ethyl acetate. The extracts were dried and the solvent was evaporated. The residue was esterified with methanol and HCl gas, then chromatographed over silica gel, the product was eluted with a mixture of ethyl acetate and hexane (30 = 70) 350 mg (37%). NMR CDCl 3 = 4.90 (cS, 1H), 4.50 (t, 1H). (b) 2-Hydroxy-5- (4-carboxyphenylthio) -3- [2- (8-phenyl-octyl) phenyl] propionic acid The compound of Example 5 (a) was hydrolyzed in the same manner as described for the preparation of compound of Example 4 (b), yielding 43% after recrystallization from a mixture of hexane and hexane. NMR (CDCl 3 / Me 2 CO) = 8.00 (d, 2H), 7.00-7.83 (m, 14H), 5.12 (d, J = 4.3Hz, 1H), 4.67 (d, J = 4.3Hz, (H), 2.40-2.90 (m, 4H), 1.76 (m, 2H). EXAMPLE 6

Preparation of 2-hydroxy-3- (4-carboxy-2-methoxyphenylmethylthio) -3- [2- (3-phenoxyphenyl) propionic acid (a) methyl 5-vratoxy-4-mercaptomethyl benzoate

A solution of 7.15 g (0.027 mol) of methyl 4-bromomethyl-3-methoxybenzoate in 50 ml of Me2 CO0 was treated with a solution of 2.1 g (0.028 mol) of thiourea in 50 ml of H2O and the reaction mixture was stirred for 24 hours. The solid iso-thioionium bromide was filtered, washed with ethyl ether - and

71 102 S3C House 3434-CIP 1 -41-dry. This salt was dissolved in 50 ml of water, treated with 50 ml of NaOH (3M) and the mixture maintained at reflux for 3 hours under argon. The clear solution was cooled, acidified and extracted with diethyl ether. The extracts were dried and treated with an ethereal solution of diazomethane for 30 minutes. Evaporation of the solvent gave methyl 3-raphoxy-4-mercaptomethylbenzate, 4.2 g (73%).

Cb) methyl 2-hydroxy-5- {4-carbomethoxy-2-methoxyphenylmethylthio 2- (8-phenyloctyl) phenylpropionate

A solution of the compound of Example 1 (c) (980 mg, 2.68 mmol) and methyl 4-mercaptomethyl-3-methoxybenzoate (625 mg, 2.95 mmol) in 10 mL of methanol and 2 mL of triethylamine, was stirred for 16 hours at 232 ° C and then evaporated. The residue was dissolved in diethyl ether and washed with 0.5 M HCl. The diethyl ether layer was dried and the solvent removed. The residue was dissolved in 15 ml of methanol, treated with 1 ml of NaOMe at 25 ° in methanol, stirred at 232 ° C for 2 hours and poured into 0.1 N HCl. The mixture was extracted with ethyl ether. The extracts were washed with water, dried and evaporated. The residue was chromatographed on silica gel. The product was eluted with a mixture of acetate and hexane (25:75) and gave 580 mg (38%), NMR (CDCl3) = 4.70 (t, J = 5.1, 50 (d, J = 5.14 Hz, 1H). (c) 2-Hydroxy-5- (4-arboxy-2-methoxyphenylmethylthio) -5- [2 - ((8-phenyloctyl) phenylpropionic acid The compound of Example 6 (b) was hydrolyzed thereto as described for the preparation of the compound of Example 4 (b), yielding 28%, after trituration with a mixture of benzene and hexane, NMR (CDCl3 / D2 O): 6.90-7.72 (m, 12H), 4.70 (d, J = 4.2, 2 Hz, 1H), 3.34-3.95 (m, 2H), 3.80 (s, 3H) , 2.20-2.68 (m, 4H), 0.98-1.88 (m, 12H).

In a similar manner the following 2? -Hydroxy-3- (5-carboxy-2-methoxyphenylmethylthio) -3- [2- (S-phenyloctyl) -phenyl] propionic acid was prepared. NMR (CDCl3): 8.16 (d, 1H), 7.90 (d, 2H), 7.5 (t, 1H), 6.88-7.22 (br. 2H), 4.76 (d, 1H), 4.48 (d, 1H), 3.81 (s, 3H), 3.70 (d, 2H), 2.00-2.60 (m, 4H), 0.67-1.62 (m, 1H). 71 102SBC Case 14343-CIF 1 Λ Ό -4a-

EXAMPLE 7

Preparation of 2-hydroxy-5- (4-carboxyphenylmethylthio) -5- [2- (8-phenyloctyl) phenyl] propionic acid (a) 2-hydroxy-5- (4-carbomethoxyphenylmethylthio) -5- [2- methyl-octyl-propyl] -ionoponate

A solution of the compound of Example 1 (e) (880 mg, 2.40 mmol) and methyl p-mercaptomethylphosphonate (525 mg, 2.88 mmol), prepared in a similar manner to the starting material of Example 6 ) in 10 ml of methanol and 0.4 ml of tristilamine was stirred at 239 for 2 days. 1 ml of NaOMe at 25 ° C methanol was added, stirring was continued for 45 minutes and the reaction mixture was poured into 0.5N HCl and extracted with methylene chloride, the extracts were dried and the solvents evaporated, the residue was chromatographed on a column of desiccated alumina (25 ml of H2 O / SO2 g of Al2 O3). The impurities were removed with a mixture of ethyl acetate and hexanes (1: 4) and the product was slurried with a mixture of methanol and ethyl acetate (1:19) and gave 620 mg (47%). 1 H-NMR (CDCl3): 4.53 (t, J = 4.5 Hz, 1H), 4.40 (d, J = 4.5 Hz, 1H). (b) 2-Hydroxy-3- (4-carboxyphenyl) ethylthio) -5- [2- (2-phenyloctyl) phenyl] propionic acid The compound of Example 7 (a) was hydrolysed in the same manner as described for Preparation of the compound of Example 4 (b), yielding 46%, after recrystallization from toluene, PMM (CDCl 3 / H 2 CO): 8.1-9.9 (broad, 3H), 8.02 (d, J = 7). , 7.62 (d, J = 7.2, 1H, 2H), 6.90-7.28 (m, 8H), 4.72 (d, J = (D, J = 4.2Hz, 1H), 3.92 (d, J = 13Hz, 1H), 3.70 (d, J = 13Hz, 1H), 2.26 - 2.70 (m, 4H), 1.02-1.76 (m, 12H). EXAMPLE 8

Preparation of 2-hydroxy-3- (2-hydroxy-5- (2-fluoro-4-carbomethoxyphenyl) methylthio (2-hydroxyethyl) -4- ) -5-methyl-2- (8-phenyloctyl) phenylpropionate

Example 1 (c) was reacted with methyl 2-fluoro-4-sec-tert -butylbenzoate, prepared in a similar manner to the starting material of Example 6 (a), in a manner analogous to that described for the preparation of the compound described in Example 6 (b) and gave the product in 22% yield. (CDCl3): 4.63 (t, J = 4.9Hz, IbS), 4.50 (d, J = 4.9Hz, 1H). (b) 2-Hydroxy-5- (2-fluoro-4-carboxyphenylmethylthio) -3- [2- (S -phenyloctyl) phenyl] propionic acid The compound of Example 3 (a) was hydrolyzed as described for the preparation of the described compound in Example 4 (b), RH (CDCl3) δ 6.98-7.90 (m, 15H), 4.68 (d, J = 4.0 Hz, 1H), Î'.55 (d, J = 6Hz, 1H), 3.80 (t, 2H), 2.25~2.7 (Î', 4H), 1.00-1.73 (m, 2H). EXAMPLE 9

Preparation of 2-methoxy-5- (4-carboxyethyl) -5- [2- (8-phenyl-octyl) phenyl] propionic acid (a) 2-methoxy-3-4- (4-carbomethoxyphenylthio) -3- [2- methylphenyl] propionate

A solution of the compound of Example 5 (a) (220 mg, 0.4 mmol) in 5 ml of tetrahydrofuran and 1 ml of dimethylformamide at 0 ° was treated with a 60% dispersion of sodium hydride in oil mineral (16 mg, 0.4 mmol). After 30 minutes, the solution was treated with iodomethane (53 mg, 0.4 mmol), stirring was continued for 1.5 hours, the reaction mixture was poured into 0.5 N HCl and extracted with diethyl ether, The extracts were dried and evaporated. The residue was initially chromatographed on alumina and eluted with a mixture of ethyl acetate and phosphazane (35:65). The residue after evaporation of the solvents was chromatographed on a silica gel column. The product was eluted with a mixture of ethyl acetate and phenoxane (1: 3) and gave 97 mg (44%). (D, J = 7.5 Hz, 1H), 3.32 (s, 3H), 3.53 (s, 3H), 3.24 (s, 3H). 71 102 SBC Case 14343-CIP 1

(B) 2-Methoxy-5- (4-carboxyphenylthio) -3- [2- (8-phenyl-octylphenyl] propionic acid The compound of Example 9 (a) was hydrolyzed in the same manner as described for the preparation of the title compound Example 4 (b), yielding 64% after trituration with a mixture of cyclohexane and

-2.9 (m, 4H), 1.18-1.90 (m, 12H).

In a similar manner the following was prepared: 2-methoxy-3- (4-carboxy-2-methoxyphenylmethylthio) -3- [2- (3-fendylactyl) phenyl] propionic acid; 2-methoxy-3- (4-carboxyphenylthio) -3- [2- (3-phenylpropyl) phenyl] propionic acid and 2-methoxy-3- (4-carboxy-2-methoxyphenylthiothio) 3- [2- (14 "-phenyltetradecyl) phenyl] propionic acid. EXAMPLE 10

Preparation of 2-hydroxy-5- (4-hydroxyphenyl) -5- [2- (8-phenyloxymethyl) phenyl] propionic acid (a) 2-hydroxy-5- (4-hydroxyphenylthio) -3- [2- 8-phenoxyethyl) propionate The compound of Example 1 (c) (722 mg, 2mmol) was dissolved in methanol (10ml) containing 2% triethylamine and the solution was stirred under argon at room temperature . Triethylamine (1.68 ml, 12-lysol) and 4-hydroxythiophenol (428 mg, 3.4 mmol) were dissolved in methanol (15 ml) and added to the reaction mixture which was then stirred overnight at environment. The solvent was evaporated and the residue flash chromatographed on 80 grams of silica gel eluted with 30% ethyl acetate / hexanes to give a mixture of the desired product and its regioisomer, 3-hydroxy-2- (4 -hydroxyphenylthio) -3- [2- (8-phenyl-octyl) phenyl] propionate. The mixture of the diastereomers was dissolved in methanol (20 ml) and stirred under argon at room temperature. Sodium methoxide, 25%, was added dropwise thereto.

-45 "psso síf; methanol (0.92 ml, 4 mmol) and the mixture stirred for 2.5 hours. The mixture was cooled in an ice bath and acetic acid (0.3 mL, 5.2 mol) was added dropwise. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give the crude product which was flash chromatographed on 80 grams of silica gel, eluting with 25% ethyl acetate / hexane to afford the desired product. (b) 2-Hydroxy-5- (4-hydroxyphenylthio) -3- [2- (8-phenyl-octylphenyl] propionic acid The compound of Example IG (a) (410 mg, 0.83 mmol) was dissolved in methanol ( (4 ml, 4 mmol) was added and the mixture stirred overnight at room temperature The solvent was evaporated and the residue was acidified Extraction with ethyl acetate followed by drying of the organic phase over anhydrous sodium sulfate, filtration and evaporation gave the crude product which was isolated from ethyl acetate / hexane to give the desired product as a white crystalline solid, mp 155-157 ° C. Analysis for C 29 H 34 O 4 S: Calc'd: C, 72.77; H, 7.16; S, 6.70. Found: C, 72.90; H , 6.91, S, 6.95 EXAMPLE 11

Preparation of 2-methoxy-5- (4-carboxy-2-methoxyphenyl) methylthio-3- [2- (3-phenyloctyl) phenyl] propionic acid (a) 2-methoxy-3- [4-carbomethoxy- (S) -phenyloctylphenyl] propionate The compound of Example 6 (b) was reacted in the same manner as for the preparation of the compound of Example 9 (a) and gave the product in 53% yield.1 H NMR (CDCl3): 4.48 (d, J = 7.2 Hz, 1H),

(B) 2-Methoxy-5- (4-carboxy-2-methoxyphenylmethylthio) -5- [2- (8-phenyloctyl) phenyl] propionic acid The compound of Example 1 (a) was hydrolyzed as desiccant for the preparation of the compound described in Example 4 (b) to give the desired product. NMR (CDCl3): 4.52 (d, J = 6.3 Hz, 1H), 4.18 (d, J = 2.3Hz, 1H), 3.86 (3H, 3.42 (s, 3H). EXAMPLE 12

Preparation of ____ 5- (4-carboxy-2-methoxyphenylmethylthio) -3- [2- (8-phenyloctyl) phenyl] propionic acid

A solution of 0.54 g (1.32 mmol) of tert-butyl 3-hydroxy-3- [2- (8-phenyloctyl) phenyl] propionate and 0.52 g (2.64 mole) of 3- 4-mercaptomethylbenzoic acid in 10 ml of methylene chloride at 0 ° was treated dropwise with 20 ml of trifluoroacetic acid. Stirring was continued at 0 ° for 4 hours and at 22 ° for 1 hour. all solvents were carefully evaporated. The residue was crystallized, first from ΗρΟ / MeCN (l4)) and then from r CC / / hexane and to afford the product, 0.26 g. 1 H NMR (CDCl 3 / Me 2 CO 3 / DMSO): 7.05-7.72 (br, 123-3), 4.52 (d of d, 1H), 4.83 (d, 1H), 4.82 (s, 3H), 4.68 (d, 1H), 2.83-2.24 (m, 2H), 2.36-2.74 (m, 43-3), 1.10-1.75 (m, 123-3). EXAMPLE 15

Preparation of methyl 2-hydroxy-5-mercapto-5-2- (3-phenyloctylphenyl) propionate (a) 2-Hydroxy-5- (4-methoxyphenylmethylthio) -5-octyl) I fc! UI '

A solution of 4.54 g (12.4 mmol) of the spoxyster of Example i (c) &amp; The mixture of 1.7 ml of triethylamine and 20 ml of methanol was stirred for 42 hours and the solvent evaporated. The residue was dissolved in diethyl ether and the residue was dissolved in dichloromethane (1.91 g, 12.4 mmol) and p-methoxybenzyl- washed with MCI Q, 1H. The organic layer was dried, and the solvent evaporated. The residue was chromatographed on an alumina column. The impurities and undesired ratios were alloyed with hexane / acetate of 71 102 cc Case 14343-CIP 1

(60: 40: 1). The resulting product was eluted with

(40: 60: 2), 2.66 g (40%). PMM

2.24-2.72 (m, 4H), 1.10-1.72 (m, 12H). (b) 2-hydroxy-5-mercapto-5- [2- (8-phenyloctyl) phenyl] propionate

A solution of 1.1 g (2.12 mmol) of the compound of Example 13 (a) in 25 ml of methanol was treated with a solution of 2.02 g (6.35 mmol) of mercuric acetate in 100 ml of methanol. After stirring for 16 hours, the white precipitate was filtered and washed with diethyl ether. This mercuric salt was dissolved in 25 ml of hot dimethylformamide, 50 ml of methanol was added and the solution was bubbled into solution M23 for 30 minutes. The black precipitate was filtered, the filtrate was concentrated, diluted with water and extracted with diethyl ether. The diethyl ether layer was washed well with water, dried, and the solvent evaporated. The crude product was chromatographed on a silica gel column and the product eluted with a mixture of ethyl acetate / hexane (40:60), 370 mg (44%). NMR (CDCl3 / P2 O) = 7.02-7.73

EXAMPLE 14

Preparation of 2-hydroxy-5- (2-undecyloxyphenyl) -5- (d-carboxyphenylthio) propionic acid (a) 2-undecyloxybenzamide To a stirred suspension of sodium hydride (10.0 mmol), which was pre-washed with ether (10 ml) was added dropwise a solution of salicylaldehyde (10.1 mmol) in dimethylformamide (1 ml). To the reaction mixture was then added undecyl bromide (10.0 mmol) and the mixture stirred for 16 hours at room temperature under nitrogen. The reaction mixture was dissolved in hexane (50 mL) and washed with 10 percent sodium hydroxide (2 x 50 mL) and

Saturated sodium chlorate (50 ml). The organic phase was dried over anhydrous magnesium sulfate and charcoal. Evaporation of the volatiles from a colorless liquid which was purified by flash chromatography on silica gel with 2% ethyl acetate in hexane as the solvents afforded the desired product as an oil.

Analysis for C18 H28 O2: Calculated C, 78.21; H, 10.21. Found: C, 77.92; H, 9.95 (b) 2-Hydroxy-3- (2-undecyloxyphenyl) -5- (5-carboxyphenylthio) propionic acid The compound of Example 14 (a) is converted to the desired product using the general procedures of Example 1 (c) -1 (e).

The following compounds are prepared according to the general procedures of Example 1 (c) -l (e) from the appropriate alkyloxyborane-aldehyde, which is prepared by the general procedure of Example 14 (a) from And the appropriate alkyl halide? 2-hydroxy-3- (2-heptyloxyphenyl) -3- (3-carboxyphenylthio) pyrroic acid; 2-Hydroxy-3- (2-dodecyloxyphenyl) -3- (3-carboxyphenylthio) propionic acid 2-hydroxy-3- (5-methoxy-2-dodecyloxyphenyl) -3- (3-carboxy- 2-hydroxy-3- (5-methyl-2-dodecyloxyphenyl) -3- (3-carboxyphenylthio) propionic acid 2-hydroxy-3- (5-fluoro-2- 2-hydroxy-3- (5-chloro-2-dodecyloxyphenyl) -3- (3-carboxyphenylthio) propionic acid 2-hydroxy-3- (3-carboxyphenylthio) propionic acid; (3-carboxyphenylthio) propionic acid, 2-hydroxy-3- (5-bromo-2-dodecyloxyphenyl) -3- (3-carboxyphenylthio) propionic acid; 2-hydroxy-3- (5-hydroxy-2-dodecyloxyphenyl) -3- (3-carbonyloxyphenylthiopropionic acid, 2-hydroxy-3- hydroxy-3- (5-nitro-2-dodecyloxyphenyl) -3- (3-carboxyphenylthio) propionic acid, 2-hydroxy-3- (5-amino-2-dodecyloxyphenyl) -3- (3- 2-hydroxy-3- (5-trifluoromethyl-2-docecyloxyphenyl) -3- (3-carboxyphenylthio) propionic acid. 2-hydroxy-3- (2-dodecylthiophenyl-3- (3-carboxyphenylthio) propionic acid is prepared from 2- (dodecylthio) benzaldehyde. 2-Hydroxy-3- (2-heptylthiophenyl) -3- (3-carboxyphenylthio) propionic acid &amp; prepared from 2- (heptylthio) benzaldehyde. EXAMPLE 15

Preparation of 2-hydroxy-3- [2- (6-phenyl-hexyl) -hexyl] -5- (5-carboxyphenylthio) propionic acid (a) 2- (6-phenylhexyloxy) benzaldehyde

A solution of 6-phenylhexanoic acid (19.8 mmol) in dry tetrahydrofuran and filtered (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 0 ° C for 4 hours to give 6-phenylhexanol. To an ice cold solution of hexanol (ca. 19.8 mmol) carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was dissolved in ether (100 ml), cooled on ice and filtered, the filtrate was evaporated and distilled to afford 3-6-phenylhexyl bromide as an oil. A mixture of bromide ( 8.00 mmol), salicylaldehyde (8.19 mmol) and potassium carbonate (9.33 mmol) in dimethylformamide (10 mL) was heated at 100 ° C and maintained at that temperature for one hour. The cooled reaction mixture was dissolved in hexane (50 ml) and washed with 5% sodium hydroxide (50 ml) and saturated sodium chloride (50 ml). The organic phase was dried over anhydrous magnesium sulfate

Carbon dioxide. Evaporation gave a colorless oil which was purified by flash chromatography on silica gel with 5% ethyl acetate in hexane as eluant to provide the desired product with an oil.

Anal. Calc'd for Câ, â,ƒHâ,,â, € 2: Calc'd C. 80.32% H, 7.85. Found: C, 80.61; H, 7.72. (b) 2-Hydroxy-3- [2- (6-phenylhexyloxy) phenyl] -5- (5-carboxyphenylthio) propionic acid The compound of Example 15 (a) is converted to the desired product by use of the general procedures of Example (c) to SC1 (e).

The following compounds are prepared according to the general procedures described above from the appropriately substituted phenylalkyloxybis-aldehyde. 2-hydroxy-3- [2- (3-phenylpropyloxy) phenyl] -3- (3-carboxy-1-ynyl) propionic acid, 2-hydroxy-3- [2- - (9-phenylnonyloxy) phenyl] -3- (3-carboxyphenylthio) propionic acid. EXAMPLE 16

Preparation of 2- (6-thiophenoxyhexylthio) benzoic acid Thiosalicylic acid (a) Preparation of 2- (6-phenylthiohexythio) phenyl] -3- (2-carboxyphenyl) 1.2 g, 0.008 mol) and 6-thiophenoxyhexyl bromide (2.5 g, 0.009 mol) are dissolved in dimethylformamide (50 ml) and the solution is stirred under argon. After the addition is complete, the mixture is slowly heated to 100 DEG C. The solvents are evaporated and the residue is dissolved in water, acidified, and dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is flash chromatographed on silica gel to give the desired product.

(B) Preparation of 2- (6-phenylthiohexylthio) benzyl alcohol To a suspension of lithium aluminum hydride (0.292 g, 0.007 sol) if tetrahydrofuran (30 ml) is added a solution of and 2- (6-thiophenoxyhexylthio) benzoic acid (2.42 g, 0.007 mol) in tetrahydrofuran (30 ml). The reaction mixture is stirred at room temperature under argon overnight. When the rationing is complete, several drops of gallate water are added, followed by cold 10% sodium hydroxide (approx. 1.0 ml), followed by cold 10% sodium hydroxide (approximately 1.0 ml), followed by further water icy This produces a dry granular precipitate which is filtered and washed. The filtrate is then dried over magnesium sulfate, filtered and evaporated. The crude alcohol is flash chromatographed on silica gel to give the desired compound, (c) Preparation of 2- (6-phthalylhexylthio) benzaldehyde To a suspension of manganese dioxide (11.73 g, 0.135 mol) in ethyl acetate (30 ml) is added a solution of 2- (6-thiophenoxyhexylthio) benzyl alcohol (1.23 g, 0.0037 mol) in ethyl acetate (20 ml). The reaction mixture is stirred at room temperature under argon for 1.5 hours. The suspension is then filtered. The filtrate is dried over magnesium sulfate, filtered, and evaporated to afford the desired compound. The compound of Example 16 (c) (10 mmol) was dissolved in dichloromethane (2 ml) and recrystallized from dichloromethane ) is dissolved in ether (25 ml) and the solution is stirred under argon at 0 ° C. was added methyl chloroacetate (15 mmol), followed by the addition of sodium methoxide (15 mmol). The mixture is stirred for 2.5 hours at ice-bath temperature. A small amount of water is added, the ether phase is separated, dried over anhydrous sodium sulfate, filtered and evaporated. The residue is flash chromatographed on 80 grams of silica gel eluted with 5-30% ethyl acetate / hexanes to give the product. (S) Γ 2 - (6-Phenylhexylthio) phenyl] -3- (2-carboxyphenylthio) -2-methyl- hydroxypropionate

A solution of the compound of Example 16 (d) (1.39 mmol), 2-mercaptobenzoic acid (1.53 mmol) and triethylamine (3.06 mmol) in 10 mL of methanol is stirred overnight at 220 ° C. under argon. The mixture is poured into water, acidified with 1N hydrochloric acid and extracted with diethyl ether. The extracts are dried and the solvent is evaporated, the residue is chromatographed on silica gel to remove the starting materials and the product is eluted with a mixture of ethyl acetate, hexane and methanol (80:40, 2.5). The residue is recrystallized from methanol to give the product.

f -c v l ·· J

3-1 2- (6-Phenylthiohexylthio) (phenyl) -2-hydroxypropylmethyl 11-

A suspension of the compound of Example 16 (e) (0.44 mmol), 5 ml of methanol, 2 ml of water and 2.5M sodium hydroxide is heated at 95 ° for 10 minutes and is stirred at 22 ° for 2 h, The mixture is diluted with 20 ml of water and filtered. The filtrate is acidified and extracted with ethyl acetate. The extracts are washed with water, dried and the solvent is evaporated. The residue is recrystallized from acetonitrile to give the desired product. EXAMPLE 17

Preparation of 2-hydroxy-3- (2-carboxy-4-oxo-8-propyl-1,414-benzopyran-7-ylthio) -5- [2- (S -phenyloctyl) phenyl] propionic acid (a) Ethyl 4 - ((dimethylamino) thioxomethoxy) -4-oxo-8-propyl-4-S-1-benzopyran-2-carboxylate Ethyl 7-hydroxy-4-oxo-5-propyl-4 (1 g) in anhydrous dimethylformamide (4 ml), cooled to 0 DEG under nitrogen was treated with sodium hydride (dispersion & 50% of mineral oil, 180 mg) with stirring over 30 minutes. Dimethylaminothiocarbamyl chloride (465 mg) is added the mixture is stirred for 15 minutes at 0 °, warmed to SOS and held at that temperature for 18 hours.

Cooled, diluted with methylene chloride (50 ml) and washed with water (3 x 100 ml), dried over sodium sulfate and reduced to dryness in vacuo. The residue is recrystallized from ethyl acetate and hexane to give the title compound. The ester prepared in Example 17 (a) is heated neat under a nitrogen atmosphere to give the title compound as a white solid (0.8 g). nitrogen to 2009 for 2 hours. After cooling, the residue is crystallized from ethyl acetate and hexane to give the title compound. (c) 7-Fluorapto-4-oxo-8 &quot; prilpyl-4H-1-benzopyran-2- (690 mg) in anhydrous methanol (50 ml), and to this mixture is added the compound of Example 17 (b). The mixture is stirred under a nitrogen atmosphere for 3 hours at ambient temperature, water (50 ml) is added and the mixture &gt; acidified with 6M HCl. The resulting crystals are collected by filtration and recrystallized from ethyl acetate to provide the title compound. (d) 5-Hydroxy-5- (2-chloro-4-oxo-8-chloro-4H-1-benzopyran-7-ylthio) -5- [2- (8-phenyloctylphenyl) propionate Compound of Example 1 c), methyl trans -3- [2- (8-phenyloctyl) phenyl] -2,3-epoxypropionate is reacted with 7-mercapto-4-oxo-4-propyl-4 ' benzopyran-2-carboxylic acid from Example 17 (c) in a manner analogous to that for the preparation of the compound of Example 1 (d) to give the desired product: (a) 2-Hydroxy-5- (2-carboxy-4-oxo-8-propyl-4H-1-benzo pyran-7-ylthio) -5- [2- (8-phenyloctyl) phenyl] propionic acid The compound of Example 18 (d) is hydrolyzed with aqueous NaOH in a manner analogous to that for the preparation of the compound of Example 1 (e) to give the desired product. -54- 71 102 SEC Case 14343-CIP 1 EXAMPLE 18

Preparation of 2-Hydroxy-5-oxo-2-phenoxyphenylmethyl- (2-hydroxy-3 - [(5-carbomethoxy-2- methoxyphenylmethyl) thio] -3- [2- (2-phenyloctyl) phenyl] propionamide The compound was prepared from the compound of Example 1 (c) in a manner analogous to the preparation of the compound of Example 6 (b).

The compound of Example 18 (a) was hydrolysed in the same manner as in Example 1 (a) to give the title compound as a white solid. than described for the preparation of the compound of Example 4 (b), after trituration with a mixture of cyclohexane and hexane,

EXAMPLE 19

Preparation of (R) -3 - [[2- (8-phenyloctyl) phenyl] propionic acid (a) (2-naphthyl) -5- [2- (8-phenylethyl) phenyl] propenone To a 3-necked flask of 12 L, equipped with vigorous overheating, a condenser and a cooling bath (52). under flow of a. (36.8 g, 1.16 M) was added to ethanol (3.53 l, 95%) over a period of 30 minutes. After stirring for 4 minutes, 2-phenyloctyl bresaldehyde was added. After completion, the reaction was cooled to 102 ° C and added in a single portion

(115-6 g, 0.679M). The reaction mixture was stirred at room temperature for 18 h, during which time a yellow solid precipitated. The reaction mixture was treated with ice water (350 ml) and cooled to 10 ° C. After stirring for 1 hour. the reaction mixture was filtered and the filter cake was washed with 50% aqueous ethanol (400 ml). The solid was air-dried, pulverized and dried in vacuo (1.5 mm at room temperature) to give 248.3 g (39%) of the title compound. f. : 41-42.52 TLC R-p = 9.55 (3: 1 methylene chloride: hexane, silica gel) HPLC-RT = 17.7 min. (taATERS wBondapak®), C-1S RP5 acetonitrile; IR (nujol slurry): 1660, 1595, 1185 cm -1 IR (CDCl3): Î'190.3, 143.3, 142.9 , 142.4, 135.6, 133.5

Elemental Analysis: Theory: C, 33.74. H, 7.675. Found: C, 88.84; H, 7.68. (b) (2R) -1 - (2-naphthyl) -3- (2- S -phenyloctyl) phenyl] trans-2,5-epoxypropan-1-one

Sodium hydroxide (255 g, 6.37æ) was dissolved in deionized water (0.65 L) which was cooled in a water bath at 14-20øC. To this solution was added as a solid, poly-L-leucine (215 g). Calcorsa (250 g, 0.531 M) was added as a solid followed by hexane (4 L). The heterogeneous mixture was stirred at room temperature for 16 hours, cooled to 10-15 ° C in an ice bath and sodium bisulfite disodium salt was added. Isodiamine in tris-acetic acid, dihydrate (5 g). Hydrogen peroxide at 30 ° C (1.126 L) was added dropwise over 1-2 hours in a manner such that the reaction temperature did not exceed 25 ° C. The hydroxide was directed down the surface

The reaction mixture is then passed through a polypropylene tube connected to a drip hopper. The reaction mixture was stirred at 20-25 ° C for 20 hours. The reaction was quenched with ethyl acetate (0.3 L) and the reaction mixture was filtered through a layered (40-50 ° C) layered Suchner funnel. The solid poly-L-leucine was washed with ethyl acetate (0.5 L) suspended in warm (40-50 ° C) ethyl acetate (1.5 L) for 10 minutes and collected.

The combined filtrates were placed in a separatory funnel and washed with three portions of water (550 ml each) and one portion of the brine (11). The organic layer was dried over magnesium sulfate (300 g) for 5 hours, filtered and evaporated (30-40 ° C, 15 minutes) to an off-white solid. The solid was crystallized by dissolution in hot hexane-toluene (95-5 v / v, 1.9 L) and filtration through a layered Buchiier funnel (40Â ° C). The solution was allowed to stand at room temperature for 1.5 hours and placed in a refrigerator (at 5 ° C) for 12 hours. The crystalline product was collected and washed with a small portion of the filtrate and cold hexane. The product was air dried for 3 hours and thereafter dried in a vacuum extractor (1 mm, 25 ° C) for 24 hours. This yielded 200 g (82%) of the title compound (96-97% e.e.).

P. f. &quot; 62-63Â ° C TLC Rf = 0.35 (CHCl3)

Mp = 0.43 (methylene chloride = hexane 3 = 1) HPLC · TC = 6.0 min. (Waters wBondapak (R) C18 RP, 3.9 mm 4 30 cm2 acetonitrile: water 9-1.2 ml / min, detection at 211 nm) RT = 12.1 min. (QP (-) - 4.5 mm X 25 cm, methanol, 0.8 1 / min, detection at 210 nm) RT of the enantiomer = 18.8 min.

Elemental Analysis; theoretical, C 85.67, H 7.40; found C 85.93, H 7.48 [c] d (c = 1, CH 2 OI 2) = -24.6; Recryx Ix, [Î ±] D = -5-26.4, [Î ±] 255 (e = 15, CH2 Cl2) = +31.1. BHC [CDCl3]: Î'193.13, 142.89, 141.47, 136.02, 133.56,

133.00, 1323495 130.47, 129.72, 129.37, 129.06, 128.93, 123.55, 128.39, 128.22, 127, 91, 127.12, 126.47, 125.56, 124.31, 123.69, 60.48, 57.67, 35.85, 32.73, 31.18, 29.39, 29.18, 29.10 (o) 2 (8) -3- [2- (3-Phenyloctyl) -pheno-trans-2,3-epoxy-2-propyl]

Methylene chloride (300 ml) was heated to reflux and m -cperoperoxybenzic acid (28 g, 0.162M, 851) was added, followed by 2 (R) -1- (2-naphthyl) -2,3- ( (29 g, 0.162 g). The reaction mixture was stirred at reflux for 4 hours, cooled to 15Â ° C, then filtered and the filtrate was removed by filtration. m-chlorobenzoic acid and the solvent evaporated. The residue was dissolved in hot isopropanol / toluene (11/1), filtered and allowed to cool to room temperature. The crystals were formed in 5 minutes. The mixture was cooled in the refrigerator overnight, filtered and air dried (25 S, 1 mm / Hg) to give 25 g (81%, 99.9% ee) of the title product .

[: -. f. s 82-8320

Specific Potions 0 (c = 1, CH 2 Cl 2) = -89.433

Elemental Analysis &quot; Theoretical, C 82.80, H 7.20; found C 82.92, H 7.09 (d) (2R) -5- (2- (8-phenyloctyl) phenyl) -2,5- (tr ans) -epoxypropionamide The ester of Example 19 c) (2.03 g) was dissolved in methanol (2 ml, 1 ml) and cooled in an ice bath. Methanol saturated with ammonia (21.1 ml) was added dropwise with an increase in temperature of 520. After 5 hours the methanol / ammonia was evaporated. The ammonia was &quot; removed by solution and evaporation from toluene. The residue was subsequently dissolved in toluene, washed with water (IX), 10% NaOH (3X), water (2X) and brine (IX). After drying over MgSO 4, the solution was filtered and the solvent evaporated. The resulting solid was dissolved in hot hexane: CH 2 Cl 2 (90:10), filtered through a hot stripped funnel, into a flash filtration filter

After being cooled to room temperature, the solid was collected by filtration and dried to give 1: 1 of the title compound.

p-rf. 80-82-2C

Analysis Elementars theory, C: 78.59, Mb 8.32, Nb 3.99; found, C = 78.35, M: 8.34, Ms 3.90, c = -12.3 (c = 1, CH 2 Cl 2) (a) ?????????????????????????????????????? (4-carbomethoxyphenyl) thiol-2-hydroxy-3- [2- (8-phenyloctyl] phenyl] propionia}

A solution of 4.9 g (0.014 mol) of the compound of Example 19 (d) in 100 ml of THF at 0O was treated with 10.4 ml (0.035 mol) of titanium isopropoxide and stirred for 30 minutes. This was then treated with a solution of 3.5 g (0.021 mol) of methyl p-mercaptobenzate in 50 ml of THF, which had been treated with 100 mg of 60% MaH. The combined solution was stirred at 0 ° C for 2 hours, poured into 400 ml of 10% H2 SO4 with Et2O. The extracts were washed with H2 O and aqueous N2 OCO3, dried over the solvent removed. The residue was chromatographed on silica gel and a quantitative recovery of the product was eluted with a mixture of 10% MeOH and 90% EtOAc. (M, 1H), 7.46 (d, 2H), 6.98-7.40 (m, SH), 6.32 (d, 2H) (d, 1H), 4.42 (t, 1H), 3.88 (s, 3H), 2.40-3.02 (m, 5H), 1.09-1.82 (m, 12H). (f) FF-fR &quot; ' , 4-carbomethoxyphenyl) -1,2-hydroxy-5- [2- (S -phenyloctyl) phenyl] propionate

A solution of 7.6 g of the compound of Example 19 (e), in a mixture of 180 ml of MeOGH, 15 ml of conc. and 10 ml of HCl 3 was refluxed for 16 hours. The MeOH was removed in the residue extracted with Et 2 O. The extracts were washed with HbO, dried and the solvent removed. The residue was chromatographed on a silica gel column and 6.4 g (89%) of the product was eluted with a mixture of 40% EtOAc and 60% hexane. 1 H-NMR (CDCl 3): 7.94 (d, 2H), 7.62 (m, 1H), 7.40 (d, 2H), 6.97-7.27 (m, 3H), 4.95 , 1 H), 4.54 (t, 1H), 3.82 (s, 3H)

(S, 3H), 3.13 (d, 1H), 2.37-2.80 (m, 4H), 1.03-1.87 (m, 111,129), â € ƒâ € ƒâ € ƒ (S) (1H-Phenyl)

A solution of 4.08 g (7.8 mmol) of the compound of Example 19 (f), a mixture of 80 ml THF and 20 ml DRF at 0Â ° C, was first treated with a slurry of 343 mg of HCl at 60 DEG (cleans the mineral oil with hexane) in 10 ml of THF and then 0.54 ml (8.6 mmol) of iodomethane. After 30 minutes, the mixture was poured into 100 ml cold 5M HCl and extracted with Et 2 O. The extracts were washed with aqueous H 2 O and NaHSO 3, dried & The residue was chromatographed on a silica gel column, 3.19 g (76%) of the product was quenched with CHCl3. NMR (CDCl3); 7.92 (d, 2H), 7.00-7.0 (m, 11H), 4.93 (d, 1H), 4.18 (d, 1H), 3.90 (s, 3H), 3. , 61 (s, 3H), 3.33 (s, 3H), 2.47-2.80 (m, 4H), 7.1-7.80 (m, 12H). (Si) Γ R 3 - (4-carbomethoxyphenyl) sulfonyl-2-methoxy-3- [2- (8-

A solution of 1.26 g (2.3 mmol) of the compound of Example 19 (g) in 100 ml of treated with a solution of 1.25 g of 80% m-chloroperbenzoic acid in 100 ml of CH2 Cl2 * ; The reaction mixture was stirred at rt for 1 hour, then washed twice with aqueous sodium hydroxide, once with aqueous hexane, then the solvent evaporated. The residue was chromatographed on a silica gel column and 1.22 g (95%) of product were eluted with CHCl3, WM (Cr> C13): Î', 03 (d, 2H), 7.53 (broad (m, 8H), 5.10 (d, 1H), 4.90 (d, 1H), 3.93 (s, 3H), 3.80 (s, 3H) , 3H), 3.52 (s, 3H), 2.03-2.80 (m, 6H), 1.00-1.6 (m, 10H). (i) (1R, 2S) -4-Carboxyphenyl) sulfonyl-2-methoxy-3- [2- (8-phenyloctyl) phenylpropionic acid

A solution of 1.22 g of the compound of Example 19 (h),

A mixture of 6 ml of glacial HCl and 3 ml of conc. HCl was maintained at reflux for 9.5 hours, cooled and poured into 150 ml of water

This solution was washed twice with r2 O, dried on the solvent evaporated, and provided 0.97 g of product. (CDCl3): Î'8.3 (d, 2H), 7.53 (br d, 3H), Î'0.7.40 (m, 8H), 5.17 (d, 1H, J = , 96 (d, 1H), 3.60 (s, 3H), 2.0 (t, 2H), 2.10-2.70 (m, 2H), 0.93-1.77 ( m, 12H). EXAMPLE 20

Preparation of (R) - (R *, S **) - 5- (4-carboxyphenyl) -1H-ol -2-msoxo-2- [6-phenylpyrimidinylpropionic acid

A solution of 177 mg of the compound of Example 19 (g) in 10 ml of HeOH was treated with 2 ml of 2.5M NaOH and stirred for 16 hours at 0 DEG C. The solution was poured into 50 ml of H2 O and filtered. The filtrate was acidified and extracted with CH2 Cl2. The extracts were washed with H2 O, dried and the solvent evaporated and gave the product, 120 g. PMM (CDCl3); 7.02 (d, 2H), 7.52 (d, 2H), 7.02-7.58 (m, 9H), 3.10 (d, 1H), 4.26 , 20 (s, 3H), 2.98 (m, 2H), 2.45 (t, 2H), 1.13-1.90 (m, 12H). EXAMPLE 21

Preparation of (R) -R- (S) -1- (4-Carboxyphenyl) -2-hydroxy-3- [2- (8-phythoxycarbonyl) phenyl] propionic acid

This compound was prepared from the compound of Example 19 (g) in exactly the same manner as Example 20 = PMM: (CDCl 3 / Me 2 CO): 8.00 (d, 2H), 7.70 (m, 1H), 7.49 (d, 2H), 7.00-7.45 (m, 8H), 5.12 (d, 1H), 4.67 (d, 1H), 2.40-2.90 (m, 4H), 1.10-1.76 (m, 12H). EXAMPLE 22

Preparation of [R - (R) -C (S) -β- (4-carboxy-2-methoxyphenylmethyl) thio] -2-hydroxy-5- [2- (8-phenyloctyl) phenyl] propionic acid (a) S * &quot;)! (4-Carbomethoxy-2-methoxyphenyl) methyl] -2-hydroxy-3- [2- (8-phenyloctyl) phenyl] propionamide

A solution of 2.76 g (13 mmol) of 4-cyclopentyloxy-2-

The title compound was prepared according to the procedure described in Example 1 (a). A solution of 3.51 g (10 mmol) of the compound of Example 19 (d) in 100 ml of CH2 Cl2 at 0 ° was treated with 7.43 ml (25 mmol) of titanium isopropoxide. The two solutions were combined, and stirred at 0 ° C for 2 hours, at 202 ° for 16 hours, and the reaction was quenched with 100 ml of 42% -3% at 10 ° C. The mixture was extracted with CH2 Cl2. The extracts were washed with H2 O, dried and the solvent evaporated. The residue was chromatographed on a silica column, and 3.4 g of the product was eluted with a mixture of 5% MeOH and 95% EtOAc. (RS) -1-3- (4-oxo-2-methoxyphenethyl) methylthiol-2-hydroxy-3- (2- (8-phenyloctyl) phenyl] propionate it

This compound is prepared from the compound of Example 22 (a), in a manner exactly analogous to the preparation of the compound of Example 19 (f). (CDCl3): 6.92-7.78 (m, 12H), 4.70 (t, 1H), 4.50 (d, 1H), 3.60-3.93 (d of d, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.60 (s, 3H), 3.30 (d, 1H), 2.53 (t, 2H) 20-2.46 (m, 2H), 0.98-1.72 (m, 2H). (c) 1 - [(4-Carboxy-2-methoxyphenylmethyl) -thiol-2-hydroxy-3- [2- (8-phenyloctyl) phenyl] propionic acid

This compound was prepared from the compound of Example 22 (b), in a manner exactly analogous to the preparation of the compound of Example 20 (CDCl 3 / Me 2 Co): 6.93-7.78 (m, 12H) , 4.76 (d, 1H), 4.53 (d, 1H), 3.92 (d, 1H), 3.24 (s, 3H) 2.69 (m, 4 H), 1.03-1.80 (m, 12 H). EXAMPLE 23

Preparation of (R *, S *) - [3- (4-carboxy-2-fluorophenyl) ethyl] -2-hydroxy-3- [2- (8-phenyloctyl) phenyl] propionic acid 3-f (4-carbomethoxy-2-fluorophenylmethyl) thio] -2-hydroxy-5- [2- (8-phenyloctyl) phenyl] propionamide This compound was prepared from

(C) in a manner exactly analogous to that of Example 22. (b) [R - (R *, S *) - 5 - [(4-carbomethoxy -2-fluorophenylmethyl) thio] -2-hydroxy-3- [2- (S -phenylthio) phenylmethylphenol

This compound was prepared from the compound of Example 23 (a), in a manner exactly analogous to the preparation of Example f.-tW (CDCl 3): 6.97-7.90 (m, 12H), 4.42-4 (M, 4H), 1.00 (m, 2H), 3.48-3.98 (m, 8H), 3.06 (d, 1H), 2.28-2.72 74 (1H, 12H). (4-Carboxy-2-fluorophenylmethyl) thio] -2-hydroxy-5- [2- (8-phenyloctyl) ethyl] ) phenylpropionic acid

This compound was prepared from the compound of Example 23 (b) in a manner exactly analogous to the preparation of the compound of Example 20. (CDCl3) = 6.98-7.90 (m, 12H), 4.68 (d , 1H), 4.55 (d, 1H), 3.60-3.92 (m, 2H), 2.20-2.70 (m, 4H), 1.02-1.76 (m, 12H ). EXAMPLE 24

1-carboxyethylphenyl) thio] -2- (8-phenyloctyl) phenyl] propionic acid 3- [4- (5-carbomethoxyethyl) ethyl] thio] -2-hydroxy- (D) and methyl m-mercaptophenylacetate were prepared in a manner analogous to the preparation of the compound of Example 22 (a) . NMR (CDCl 3): 7.58-7.32 (m, 1M), 6.96-7.52 (m, 12H), 6.39 (broad d, 1H), 3.62 (broad d, 1H) , 3.05 (d, 1H), 4.37 (t, 1H), 4.03 (d, 1H), 3.7 (s, 3H) 3.02 (m, 4H), 1.18-1.82 (m, 12H). (b) Methyl (R, S) -5- (3-carbomethoxymethylphenyl) thio] -2-hydroxy-3- [2- (8-phenyl-octyl) phenyl] propionic acid methyl ester

Lst-s compound was prepared from the compound of Example 71

24 (a), in a manner analogously to the preparation of the compound of Example 19 (f). (e) -3- (5-Carbostymethylphenyl) thio-2-hydroxy-5-tetrazolophenylpropionic acid The title compound was prepared from the compound of Example 24 (b) ), in a manner exactly analogous to the preparation of the compound of Example 20

EXAMPLE 25

As a specific embodiment of a composition of this invention, 1 to 10 mg / ml of an active ingredient, such as the compound of Example 1, is dissolved in isotonic and aerosolized saline solution from a nebulizader operating at an air flow adjusted to deliver the desired aerosolized weight of medicament. EXAMPLE 26

As a further embodiment of a composition thereof? 100 mg of an active ingredient, such as the compound of Example 4, 13 or 14, are combined with 4 mg of chlorpheniramine maleate with a suitable carrier or excipient.

Claims (8)

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof-R (3) or (2) R1 is (l) a - (CH2) b is 0 or i; is 3 to 14; c is 0 or 1; L and T are independently oxygen or CH2, M is C1-4 alkyl, ethynyl, trifluoromethyl, isopropenyl, furanyl, thienyl, cyclohexyl or phenyl, optionally monosubstituted with Sr, Cl, CF3, C2-4 alkoxy , methylthio or trifluoromethylthio, Y is (CH 2) p-2 wherein C 3 is OH, NH 2, aryloxy or alkoxy p is 0, 1 or 2%, or OH or alkoxy Z is COR 3 or tstrazolyl; R s - (CH 2) p W; d is 0 to 6; H is phenyl substituted with B, C or D5 is - (C: -b) p and p is 0 to 6 and V is COR3, SO3 H, 302, SG2 MH2, COCS-bOH, CHQHCH2 O or tetrazolium , wherein R 3 is defined as C1-4 alkyl, C1-4 alkoxy, methylthio, trifluoromethyl, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, C1-4 alkoxy, (CH 2) d -COOR 3, which may be the same as that of the compound of the formula (XIV) Wherein X is OH, R 3 and R 4 are defined as above, are independently selected from C 1-4 alkyl to give a thiol represented by the structural formula al (XV) below (XI), and the reaction of the thiol of formula (XV) with an alkylating agent to give a compound of formula (I) or (8) reacting the thiol of formula (XV) with a Hieloel acceptor to give a compound of formula I wherein: (c) reacting an epoxide of formula XVI XVI) with an HS-R group, in the presence of a titanium tetra-alkoxide ΊΙ 102 to give a compound of formula (I) wherein K is OH; or D) etherifying a compound of formula XVII where C, D, p and d are defined as above, with an alkanol I or E) oxidation of the sulfur of a compound of formula (XVIII) (XVIII) wherein X is -OH or C1-4 alkoxy and R1, R2, B and D are defined as above, then optionally forming a pharmaceutically acceptable salt. A process as claimed in claim 1, wherein the group HS-R is HS- (CH 2) d -G 1 'D wherein d is 1 or 2 and S 1 and C 2 are as defined above titanium alkoxide is titanium isopropoxide. A process according to any one of claims 1 or 2 wherein X is 2, X is OS-β or alkoxy, E, C, D, 2, ρ and d are defined as above in Claim 71 14343-CIP 1-α-Ι, or a pharmaceutically acceptable salt thereof. The cis process according to claim 3, characterized in that the compound of the formula (I) is (are) 0 to 1; be COR3. A compound according to claim 4, characterized in that the compound prepared is [2- (2R, 3S) -3-3- (4-Carboxyphenyl) sulfonyl] -2-methoxy-3- [2- - (3-phenyloctyl) phenyl] propionic acid or a pharmaceutically acceptable salt thereof. A process according to claim 2, wherein X is OH, or C 1-4 alkoxy, R 1, B, C, D, 2, p and d are as defined in claim 1, or a pharmaceutically acceptable salt thereof; is acceptable to you, 7. A process according to claim 6, wherein X is -001-¾, Z is COR3, d is 0 or 1, and are C and M are COR3, 7. A process according to claim 7, wherein the compound prepared is [R- (R, 3 S) -3-3 - [(4-carboxyphenyl) thio] -2-methoxy-3- - [2- (8-phenyloctyl) phenyl] propionic acid or a variant thereof. 9. A process for the preparation of a pharmaceutical composition according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof, prepared according to the invention is combined with a pharmaceutically acceptable carrier. Lisbon. 12. JUN. 1990 By SMITHKLINE BEECHAM CORPORATION - 0 OFFICIAL AGENT -